Coordinate Expression of Colony-Stimulating Factor-1 and Colony-Stimulating Factor-1-Related Proteins Is Associated with Poor Prognosis in Gynecological and Nongynecological Leiomyosarcoma

Abstract

Previously, we showed that the presence of high numbers of macrophages correlates with poor prognosis in nongynecological leiomyosarcoma (LMS). In gynecological LMS, a similar trend was noted but did not reach statistical significance. Colony-stimulating factor-1 (CSF1) is a major chemoattractant for macrophages. Here we show that in a subset of LMS cases, CSF1 is expressed by the malignant cells. Previously, we found that CSF1 is translocated and highly expressed in tenosynovial giant cell tumors (TGCTs), and this observation allowed us to identify genes that showed a coordinate expression with CSF1. Here, we evaluated the expression of CSF1 and TGCT-associated proteins in 149 cases of LMS. The coordinate expression of CSF1 and three TGCT-associated proteins (CD163, FCGR3a, and CTSL1) identified cases with poor prognosis in both gynecological LMS (P ‫؍‬ 0.00006) and nongynecological LMS (P ‫؍‬ 0.03). In gynecological LMS, the coordinate expression of these four markers was the only independent prognosticator in multivariate analysis (hazard ratio, 4.2; 95% CI, 1.12 to 16; P ‫؍‬ 0.03). Our findings indicate that CSF1 may play an important role in the clinical behavior of LMS that may open a window for new therapeutic reagents.

Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma

“…The TME's role as a nonneoplastic component of tumors has been studied extensively in carcinomas but remains less well characterized in sarcomas. Consistent with the findings in carcinomas, we have previously shown that in LMS, a high density of TAMs predicts poor patient outcome, and that these TAMs are likely attracted to the primary tumor site by secretion of the macrophage chemoattractant colony-stimulating factor-1 (CSF1) by tumor cells (7,8). Moreover, in extrauterine LMS, we showed a correlation between CSF1 expression and a highly vascularized TME, consistent with the protumorigenic effects of TAMs (9).…”

“…TAM infiltration was likely mediated by expression of CSF1 by the tumor cells. In nongynecological LMS, the presence of TAMs was associated with increased vessel density, suggesting that the poor clinical outcome seen in these tumors could in part be because of increased vascularity mediated by TAMs (7)(8)(9). Hence, the M2 phenotype likely predominates in TAMs present in LMS tumors as it does in most, but not all, epithelial tumors.…”

Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3

“…We previously demonstrated that CD163 is a useful marker for detecting M2 cells on paraffinembedded surgical specimens (6), and high infiltration of M2 TAMs are associated with a poor clinical prognosis in patients with high grade glioma, cholangiocarcinoma, angioimmunoblastic T cell lymphoma, and renal cell carcinoma (7)(8)(9). Similar results have been reported in melanoma, follicular lymphoma, leiomyosarcoma, and pancreatic cancer (10)(11)(12). Therefore, it is speculated that the inhibition of macrophage polarization toward the M2 phenotype could represent a new strategy for anticancer therapy.…”

T‐cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death‐ligand 1 expression in patients with soft tissue sarcomas

“…Conversely, the findings of the current study suggest that LMS is an inflammatory tumor type with high levels of T‐cell‐related gene expression, with several tumors demonstrating very strong expression of PD‐L1 and containing PD‐1‐expressing cells. Nevertheless, we suspect that combination therapy may be necessary to treat these tumors because other investigators have suggested that immunosuppressive tumor‐associated macrophages may be critical to immune evasion in these tumors 29, 41, 42. Combinations of checkpoint inhibitors with drugs aimed at depleting or modulating these cells may prove successful in providing durable responses for these patients.…”