OTAR3088/BioData-CL_Article-Sentences · Datasets at Hugging Face

PMCID string	Title string	Sentences string
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	We found that MIF/CXCR4 LR was the most common crosstalk between tumor cells and macrophages in G01 and G02 ( Figures 4 – 6 ).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Interactions numbers and interaction weights of cell-to-cell. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Numbers of interactions in G01. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Weights of interactions in G01. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Numbers of interactions in G02. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Weights of interactions in G2.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	G01, high risk GIST; G02, very low risk GIST.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Outgoing and incoming signaling patterns of Cell-Chat in G01.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Outgoing and incoming signaling patterns of Cell-Chat in G02.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	MIF/CXCR4 axis was the most crosstalk ligand-receptor between tumor cells and macrophages in G01 (A) and G02 (B).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	LR interactions between tumor cells and other cells play an important role in tumor proliferation, metastasis, and progression.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Thus, the MIF/CXCR4 signaling axis between tumor cells and macrophages was selected for further investigation.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	In this study, 80 patients were included for immunohistochemistry.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Their clinicopathological characteristics are presented in Table 3 .
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	In these patients, 56 tumors were located in the stomach and 24 tumors were located in the intestine.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Fourteen patients were classified as the very-low-risk group (LG), 31 patients were classified as the intermediate-risk group (MG), and 35 patients were classified as the high-risk group (HG).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Clinicopathological characteristics of 80 patients for immunohistochemistry.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Immunohistochemistry and immunofluorescence were performed ( Figures 7 , 8 ).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Among the three groups, CD8+ T cells were the most abundant in the LG (LG vs. MG vs. HG: 0.35 ± 0.15 vs. 0.27 ± 0.10 vs. 0.09 ± 0.02, P = 0.003), whereas CD68 macrophages were the most abundant in the HG (LG vs. MG vs. HG: 0.38 ± 0.09 vs. 0.64 ± 0.17 vs. 0.98 ± 0.19, P = 0.03) ( Figure 9A ).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The expression of CD206 in the HG was the highest among the three groups (LG vs. MG vs. HG: 0.04 ± 0.01 vs. 0.07 ± 0.02 vs. 0.15 ± 0.03, P < 0.001).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Such a phenomenon was also found in MIF expression and CXCR4 expression.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Namely, among the three groups, the expression levels of MIF and CXCR4 were the highest in the HG (LG vs. MG vs. HG: 0.43 ± 0.24 vs. 0.90 ± 0.68 vs. 1.64 ± 0.53, P < 0.001; LG vs. MG vs. HG: 0.009 ± 0.003 vs. 0.70 ± 0.02 vs. 0.12 ± 0.03, P < 0.001) ( Figure 9B ).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Summarily, CD8, CD68, CD206, MIF, and CXCR4 expression are related with tumor progression.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Immunohistochemical characterization of CD8, CD68, MIF, CD206 and CXCR4 in GIST samples. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Immunofluorescence showed that co-expression of CD68 and CXCR4 in GIST sample. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Immunofluorescence showed that MIF expression is present both inside and outside GIST cells. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	(A) There were differences in CD8+T cell infiltration among different groups (0.35 ± 0.15 vs 0.27 ± 0.10 vs 0.09 ± 0.02, P=0.003); (B) There were differences in the infiltration of CD68+macrophage cells among different groups (0.38 ± 0.09 vs 0.64 ± 0.17 vs 0.98 ± 0.19, P=0.03). (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	(A) As the risk increases, the expression of CXCR4 gradually increases, and the difference is statistically significant (0.43 ± 0.24 vs 0.90 ± 0.68 vs 1.64 ± 0.53, P<0.001); (B) As the risk increases, the expression of MIF gradually increases, and the difference is statistically significant (0.009 ± 0.003 vs 0.70 ± 0.02 vs 0.12 ± 0.03, P<0.001); (C) As the risk increases, the expression of CD206 gradually increases, and the difference is statistically significant (0.04 ± 0.01 vs 0.07 ± 0.0.02 vs 0.15 ± 0.03, P<0.001); The statistical method is non-parametric test, n=80, P<0.05; *P<0.01.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Previous data have shown high expression of MIF in GIST tissues.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	To determine whether GIST-882 cell line secretes MIF, we performed an ELISA trial.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	As expected, GIST-882 cell line secreted MIF, and MIF gradually increased with time.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	When we administered ISO-1 (MIF inhibitor) to the GIST-882 cell line, secretion of MIF decreased ( Figure 10 ). (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	GIST882 cells could express CD117; (B) GIST-882 cells could secrete MIF and MIF increased gradually along with the time.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	ISO-1 could inhibit the secretion of MIF.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	To explore the effect of GIST-882 cell line on macrophages in vitro, the cell supernatant was collected as conditioned medium (CM), cultured to M0 macrophages.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Compared with the control group, M2 macrophages increased in the GIST882 CM group.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	However, when we administered ISO-1, M2 macrophages decreased.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The difference between the two groups suggested that MIF was a factor to modulate M2 polarization of macrophages.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Interestingly, when we administered WZ811 (CXCR4 antagonist), M2 macrophages also decreased ( Figures 11A, B ). (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	(A) GIST882 CM group; (B) GIST882 CM+ISO-1 group; Ctrl group vs GIST882 CM group, 1.6% vs 27.3%, P=0.000; GIST882 CM group vs GIST882 CM+ISO-1 group,27.3% vs 11.9%, P=0.006; ISO-1:MIF inhibitor; The statistical method is chi square test, **:P<0.01. (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	(A) GIST882CM group; (B) GIST882CM+WZ811 group.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Ctrl vs GIST882CM group:1.6% vs 24.8%, P=0.000; GIST882CM group vs GIST882CM+WZ811group:24.8% vs 9.3%, P=0.004; WZ811:CXCR4 antagonists; The statistical method is chi square test, **:P<0.01.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	To further confirm the polarization of M2 macrophages, IL-10 mRNA and Arginase-1 mRNA were detected.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The expression levels of IL-10 mRNA and Arginase-1 mRNA were in concordance with the results of flow cytometry, and were the highest in the GIST882 CM group ( Figure 12 ). (
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Ctrl vs GIST882CM vs GIST882CM +ISO-1 vs GIST882CM +WZ811:1.17 ± 0.43 vs 5.40 ± 1.21 vs 1.17 ± 0.23 vs 1.57 ± 0.57; (B) Ctrl vs GIST882CM vs GIST882CM +ISO-1 vs GIST882CM +WZ811:1.05 ± 0.18 vs 1.83 ± 0.18 vs 0.84 ± 0.30 vs 0.80 ± 0.17; ISO-1: MIF inhibitor; WZ811: CXCR4 antagonists; The statistical method is T-test, mean ± SEM, n=3, P<0.05; *P<0.01.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The incidence of GIST is 1.1 per 100,000, and accounts for 80% of all gastrointestinal sarcomas (22, 23).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The most common sites for GIST are the stomach (60%) and the small intestine (30%) (2, 24).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Given that mutations in KIT or PDGFRA have been identified, the treatment strategy for GIST is targeted therapy.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Imatinib, sunitinib, regorafenib, and ripretinib have been approved for the treatment of GIST.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Imatinib, the first-line system therapy, achieves an excellent disease control in 80% of patients (25).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	However, drug resistance is the most challenging clinical problem.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	As the new era of immunotherapy has arrived, the microenvironment of GIST and the roles of infiltrating cells in tumor surveillance and tumor progression should be clarified.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	CD3 T cells and macrophages have been found as the most abundant tumor-infiltrating immune cells in GIST (11, 12).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Our results revealed that CD8 T cells and macrophages were the most abundant tumor-infiltrating immune cells.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	We also analyzed the differences among LG, MG, and HG.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The results showed that macrophages were increased and CD8 T cells were exhausted with tumor progression, which is similar to other studies (11, 18).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	High infiltration of macrophages predicts poor prognosis in multiple types of tumors and is considered the reason of suppressed antitumor inflammatory setting (26–28).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	PD-1 expression by tumor-associated macrophages has been linked to inhibition of phagocytosis and immunity (29).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The M1/M2 polarization states of macrophages play an important role in tumor progression (30).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The inflammatory M1 state and protumor M2 state originate from different environmental stimuli (31).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	However, PD-1 expression has been found in M2-state tumor-associated macrophages (29).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	This discovery could explain the promotion of tumor progression by M2 macrophages.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	To clarify the polarization of macrophages in GIST, CD206 expression was examined.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	We showed that CD206 expression was the highest in the HG.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	However, the reason for the increase in tumor-infiltrating M2 macrophages in the high-risk GIST was not clear.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	So, we performed a CellChat analysis to clarify the crosstalk types between tumor cells and macrophages based on single-cell RNA sequencing data (32).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Through CellChat, we quantitatively inferred and analyzed intercellular communication networks.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The CellChat results showed that the MIF/CXCR4 axis was the main crosstalk type between tumor cells and macrophages.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	High expression of MIF has been found in many tumor tissues, such as breast cancer, lung cancer, and melanoma (33–35).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	It has also been revealed that high expression of MIF is closely related to tumor progression and metastasis (36).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	MIF could act on corresponding cells in autocrine or paracrine manner, resulting in changes in physiological functions.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Currently, four receptors for MIF have been discovered, namely CD74, CXCR2, CXCR4, and CXCR7 (37–40).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The MIF/CXCR4 axis has been found to contribute to cell survival, drug resistance, and tumor metastasis in multiple types of tumors (41–43).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	In ELISA trial, we found that GIST882 cells were able to secrete MIF, and immunohistochemical expression of MIF and CXCR4 was related to the recurrence risk.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	These results suggest that the MIF/CXCR4 axis could play a key role in GIST progression.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	In vitro, we found that the MIF/CXCR4 axis contributed to M2 polarization of macrophages.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The expression levels of MIF and CXCR4 have been identified as adverse prognostic factors in multiple types of tumors (43–45).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The MIF/CXCR4 axis could contribute to drug resistance in tumor invasion and metastasis (41, 43).
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	However, the mechanism of the MIF/CXCR4 axis in this process is unclear.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	Our results provide an idea to explain this phenomenon and stimulate further research.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	In conclusion, macrophages are the most abundant infiltrating cells in GIST.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	The MIF/CXCR4 axis is the most ligand–receptor interaction between macrophages and tumor cells.
PMC11502962	Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape	GIST cells can regulate macrophage M2 polarization through the MIF/CXCR4 axis to form an immunosuppressive microenvironment.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Phosphodiesterase 3A (PDE3A) is an emerging therapy target in various cancers with high expression, as in the majority of gastrointestinal stromal tumors (GISTs).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	However, its association with clinicopathological factors and patient survival in GISTs remains unexplored.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	We investigated PDE3A expression using a novel mouse monoclonal antibody and immunohistochemistry in two GIST patient series consisting of 173 formalin-fixed, paraffin-embedded tissue samples on tissue microarrays.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	In addition, we analyzed the association between PDE3A staining intensity and clinicopathological variables and patient survival.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	We also assessed PDE3A mRNA expression using qPCR in a subset of the samples.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	We found that all GISTs expressed PDE3A.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	The staining pattern was weak in 6.3%, intermediate in 35.8%, and strong in 57.8% of tumors.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Weak PDE3A expression was associated with a lower median mitotic count (1/50 HPF vs. 4/50 HPF vs. 5/50 HPF; p = 0.007) and higher incidence of metastases at diagnosis (28% vs. 8% vs. 3.3%; p = 0.040) than in tumors with intermediate or strong expression, respectively.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	PDE3A and CD117 staining intensities correlated positively (p < 0.001), but PDE3A expression showed no association with sex, age, tumor size, location, risk stratification, mutation profile, Schlafen 12 expression, or metastasis-free or overall survival.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	We conclude that PDE3A expression can be reliably assessed in archived tumor material using immunohistochemistry.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	GISTs, with their consistently high PDE3A expression, are a promising target for PDE3A-targeted therapies.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	This method may also aid in stratifying patients in cancers where PDE3A expression is less common.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal soft-tissue sarcoma with an annual incidence of 10 to 20 persons per million persons .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	GIST is characterized by mutually exclusive gain-of-function mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA) oncogenes in ~ 85% of cases .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	These mutations in receptor tyrosine kinase-encoding genes lead to ligand-independent constitutive activation of the kinases, driving uncontrolled tumor cell proliferation and survival .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	In addition, the mutated receptors serve as key therapeutic targets for tyrosine kinase inhibitors such as imatinib, sunitinib, regorafenib, ripretinib, and avapritinib .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	However, the specific mutation type has a marked impact on therapy sensitivity of GISTs, and secondary resistance to therapies frequently evolves during treatment .

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

We found that MIF/CXCR4 LR was the most common crosstalk between tumor cells and macrophages in G01 and G02 ( Figures 4 – 6 ).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Interactions numbers and interaction weights of cell-to-cell. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Numbers of interactions in G01. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Weights of interactions in G01. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Numbers of interactions in G02. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Weights of interactions in G2.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

G01, high risk GIST; G02, very low risk GIST.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Outgoing and incoming signaling patterns of Cell-Chat in G01.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Outgoing and incoming signaling patterns of Cell-Chat in G02.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

MIF/CXCR4 axis was the most crosstalk ligand-receptor between tumor cells and macrophages in G01 (A) and G02 (B).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

LR interactions between tumor cells and other cells play an important role in tumor proliferation, metastasis, and progression.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Thus, the MIF/CXCR4 signaling axis between tumor cells and macrophages was selected for further investigation.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

In this study, 80 patients were included for immunohistochemistry.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Their clinicopathological characteristics are presented in Table 3 .

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

In these patients, 56 tumors were located in the stomach and 24 tumors were located in the intestine.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Fourteen patients were classified as the very-low-risk group (LG), 31 patients were classified as the intermediate-risk group (MG), and 35 patients were classified as the high-risk group (HG).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Clinicopathological characteristics of 80 patients for immunohistochemistry.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Immunohistochemistry and immunofluorescence were performed ( Figures 7 , 8 ).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Among the three groups, CD8+ T cells were the most abundant in the LG (LG vs. MG vs. HG: 0.35 ± 0.15 vs. 0.27 ± 0.10 vs. 0.09 ± 0.02, P = 0.003), whereas CD68 macrophages were the most abundant in the HG (LG vs. MG vs. HG: 0.38 ± 0.09 vs. 0.64 ± 0.17 vs. 0.98 ± 0.19, P = 0.03) ( Figure 9A ).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The expression of CD206 in the HG was the highest among the three groups (LG vs. MG vs. HG: 0.04 ± 0.01 vs. 0.07 ± 0.02 vs. 0.15 ± 0.03, P < 0.001).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Such a phenomenon was also found in MIF expression and CXCR4 expression.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Namely, among the three groups, the expression levels of MIF and CXCR4 were the highest in the HG (LG vs. MG vs. HG: 0.43 ± 0.24 vs. 0.90 ± 0.68 vs. 1.64 ± 0.53, P < 0.001; LG vs. MG vs. HG: 0.009 ± 0.003 vs. 0.70 ± 0.02 vs. 0.12 ± 0.03, P < 0.001) ( Figure 9B ).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Summarily, CD8, CD68, CD206, MIF, and CXCR4 expression are related with tumor progression.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Immunohistochemical characterization of CD8, CD68, MIF, CD206 and CXCR4 in GIST samples. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Immunofluorescence showed that co-expression of CD68 and CXCR4 in GIST sample. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Immunofluorescence showed that MIF expression is present both inside and outside GIST cells. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

(A) There were differences in CD8+T cell infiltration among different groups (0.35 ± 0.15 vs 0.27 ± 0.10 vs 0.09 ± 0.02, P=0.003); (B) There were differences in the infiltration of CD68+macrophage cells among different groups (0.38 ± 0.09 vs 0.64 ± 0.17 vs 0.98 ± 0.19, P=0.03). (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

(A) As the risk increases, the expression of CXCR4 gradually increases, and the difference is statistically significant (0.43 ± 0.24 vs 0.90 ± 0.68 vs 1.64 ± 0.53, P<0.001); (B) As the risk increases, the expression of MIF gradually increases, and the difference is statistically significant (0.009 ± 0.003 vs 0.70 ± 0.02 vs 0.12 ± 0.03, P<0.001); (C) As the risk increases, the expression of CD206 gradually increases, and the difference is statistically significant (0.04 ± 0.01 vs 0.07 ± 0.0.02 vs 0.15 ± 0.03, P<0.001); The statistical method is non-parametric test, n=80, *P<0.05; **P<0.01.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Previous data have shown high expression of MIF in GIST tissues.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

To determine whether GIST-882 cell line secretes MIF, we performed an ELISA trial.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

As expected, GIST-882 cell line secreted MIF, and MIF gradually increased with time.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

When we administered ISO-1 (MIF inhibitor) to the GIST-882 cell line, secretion of MIF decreased ( Figure 10 ). (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

GIST882 cells could express CD117; (B) GIST-882 cells could secrete MIF and MIF increased gradually along with the time.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

ISO-1 could inhibit the secretion of MIF.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

To explore the effect of GIST-882 cell line on macrophages in vitro, the cell supernatant was collected as conditioned medium (CM), cultured to M0 macrophages.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Compared with the control group, M2 macrophages increased in the GIST882 CM group.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

However, when we administered ISO-1, M2 macrophages decreased.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The difference between the two groups suggested that MIF was a factor to modulate M2 polarization of macrophages.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Interestingly, when we administered WZ811 (CXCR4 antagonist), M2 macrophages also decreased ( Figures 11A, B ). (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

(A) GIST882 CM group; (B) GIST882 CM+ISO-1 group; Ctrl group vs GIST882 CM group, 1.6% vs 27.3%, P=0.000; GIST882 CM group vs GIST882 CM+ISO-1 group,27.3% vs 11.9%, P=0.006; ISO-1:MIF inhibitor; The statistical method is chi square test, **:P<0.01. (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

(A) GIST882CM group; (B) GIST882CM+WZ811 group.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Ctrl vs GIST882CM group:1.6% vs 24.8%, P=0.000; GIST882CM group vs GIST882CM+WZ811group:24.8% vs 9.3%, P=0.004; WZ811:CXCR4 antagonists; The statistical method is chi square test, **:P<0.01.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

To further confirm the polarization of M2 macrophages, IL-10 mRNA and Arginase-1 mRNA were detected.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The expression levels of IL-10 mRNA and Arginase-1 mRNA were in concordance with the results of flow cytometry, and were the highest in the GIST882 CM group ( Figure 12 ). (

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Ctrl vs GIST882CM vs GIST882CM +ISO-1 vs GIST882CM +WZ811:1.17 ± 0.43 vs 5.40 ± 1.21 vs 1.17 ± 0.23 vs 1.57 ± 0.57; (B) Ctrl vs GIST882CM vs GIST882CM +ISO-1 vs GIST882CM +WZ811:1.05 ± 0.18 vs 1.83 ± 0.18 vs 0.84 ± 0.30 vs 0.80 ± 0.17; ISO-1: MIF inhibitor; WZ811: CXCR4 antagonists; The statistical method is T-test, mean ± SEM, n=3, *P<0.05; **P<0.01.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The incidence of GIST is 1.1 per 100,000, and accounts for 80% of all gastrointestinal sarcomas (22, 23).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The most common sites for GIST are the stomach (60%) and the small intestine (30%) (2, 24).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Given that mutations in KIT or PDGFRA have been identified, the treatment strategy for GIST is targeted therapy.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Imatinib, sunitinib, regorafenib, and ripretinib have been approved for the treatment of GIST.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Imatinib, the first-line system therapy, achieves an excellent disease control in 80% of patients (25).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

However, drug resistance is the most challenging clinical problem.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

As the new era of immunotherapy has arrived, the microenvironment of GIST and the roles of infiltrating cells in tumor surveillance and tumor progression should be clarified.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

CD3 T cells and macrophages have been found as the most abundant tumor-infiltrating immune cells in GIST (11, 12).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Our results revealed that CD8 T cells and macrophages were the most abundant tumor-infiltrating immune cells.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

We also analyzed the differences among LG, MG, and HG.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The results showed that macrophages were increased and CD8 T cells were exhausted with tumor progression, which is similar to other studies (11, 18).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

High infiltration of macrophages predicts poor prognosis in multiple types of tumors and is considered the reason of suppressed antitumor inflammatory setting (26–28).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

PD-1 expression by tumor-associated macrophages has been linked to inhibition of phagocytosis and immunity (29).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The M1/M2 polarization states of macrophages play an important role in tumor progression (30).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The inflammatory M1 state and protumor M2 state originate from different environmental stimuli (31).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

However, PD-1 expression has been found in M2-state tumor-associated macrophages (29).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

This discovery could explain the promotion of tumor progression by M2 macrophages.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

To clarify the polarization of macrophages in GIST, CD206 expression was examined.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

We showed that CD206 expression was the highest in the HG.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

However, the reason for the increase in tumor-infiltrating M2 macrophages in the high-risk GIST was not clear.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

So, we performed a CellChat analysis to clarify the crosstalk types between tumor cells and macrophages based on single-cell RNA sequencing data (32).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Through CellChat, we quantitatively inferred and analyzed intercellular communication networks.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The CellChat results showed that the MIF/CXCR4 axis was the main crosstalk type between tumor cells and macrophages.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

High expression of MIF has been found in many tumor tissues, such as breast cancer, lung cancer, and melanoma (33–35).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

It has also been revealed that high expression of MIF is closely related to tumor progression and metastasis (36).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

MIF could act on corresponding cells in autocrine or paracrine manner, resulting in changes in physiological functions.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Currently, four receptors for MIF have been discovered, namely CD74, CXCR2, CXCR4, and CXCR7 (37–40).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The MIF/CXCR4 axis has been found to contribute to cell survival, drug resistance, and tumor metastasis in multiple types of tumors (41–43).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

In ELISA trial, we found that GIST882 cells were able to secrete MIF, and immunohistochemical expression of MIF and CXCR4 was related to the recurrence risk.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

These results suggest that the MIF/CXCR4 axis could play a key role in GIST progression.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

In vitro, we found that the MIF/CXCR4 axis contributed to M2 polarization of macrophages.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The expression levels of MIF and CXCR4 have been identified as adverse prognostic factors in multiple types of tumors (43–45).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The MIF/CXCR4 axis could contribute to drug resistance in tumor invasion and metastasis (41, 43).

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

However, the mechanism of the MIF/CXCR4 axis in this process is unclear.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

Our results provide an idea to explain this phenomenon and stimulate further research.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

In conclusion, macrophages are the most abundant infiltrating cells in GIST.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

The MIF/CXCR4 axis is the most ligand–receptor interaction between macrophages and tumor cells.

PMC11502962

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape

GIST cells can regulate macrophage M2 polarization through the MIF/CXCR4 axis to form an immunosuppressive microenvironment.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Phosphodiesterase 3A (PDE3A) is an emerging therapy target in various cancers with high expression, as in the majority of gastrointestinal stromal tumors (GISTs).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

However, its association with clinicopathological factors and patient survival in GISTs remains unexplored.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

We investigated PDE3A expression using a novel mouse monoclonal antibody and immunohistochemistry in two GIST patient series consisting of 173 formalin-fixed, paraffin-embedded tissue samples on tissue microarrays.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

In addition, we analyzed the association between PDE3A staining intensity and clinicopathological variables and patient survival.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

We also assessed PDE3A mRNA expression using qPCR in a subset of the samples.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

We found that all GISTs expressed PDE3A.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

The staining pattern was weak in 6.3%, intermediate in 35.8%, and strong in 57.8% of tumors.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Weak PDE3A expression was associated with a lower median mitotic count (1/50 HPF vs. 4/50 HPF vs. 5/50 HPF; p = 0.007) and higher incidence of metastases at diagnosis (28% vs. 8% vs. 3.3%; p = 0.040) than in tumors with intermediate or strong expression, respectively.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

PDE3A and CD117 staining intensities correlated positively (p < 0.001), but PDE3A expression showed no association with sex, age, tumor size, location, risk stratification, mutation profile, Schlafen 12 expression, or metastasis-free or overall survival.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

We conclude that PDE3A expression can be reliably assessed in archived tumor material using immunohistochemistry.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

GISTs, with their consistently high PDE3A expression, are a promising target for PDE3A-targeted therapies.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

This method may also aid in stratifying patients in cancers where PDE3A expression is less common.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal soft-tissue sarcoma with an annual incidence of 10 to 20 persons per million persons .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

GIST is characterized by mutually exclusive gain-of-function mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA) oncogenes in ~ 85% of cases .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

These mutations in receptor tyrosine kinase-encoding genes lead to ligand-independent constitutive activation of the kinases, driving uncontrolled tumor cell proliferation and survival .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

In addition, the mutated receptors serve as key therapeutic targets for tyrosine kinase inhibitors such as imatinib, sunitinib, regorafenib, ripretinib, and avapritinib .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

However, the specific mutation type has a marked impact on therapy sensitivity of GISTs, and secondary resistance to therapies frequently evolves during treatment .