The immune landscape of uterine leiomyosarcomas

Personalized immune intervention to release and redirect the T cells against a tumor has shown substantial progress in aggressive tumors such as melanoma and lung cancer, despite the fact that predictors of sustained response are still unclear. Data on less common histotypes are scanty. Among soft tissue sarcomas, uterine leiomyosarcomas (ULMS) have a dire prognosis, yet therapeutic advances are needed in order to improve the actual treatment. Immune checkpoint inhibitor therapy has been applied to exceptionally few cases, of which the immune cell composition was not examined in detail. We analyzed in situ the inflammatory infiltrate of 21 untreated ULMS in high-dimensional, single cell phenotyping on routinely processed tissue, directed at the characterization of lymphoid cells and macrophages. T-lymphoid cells displayed a composite phenotype common to all tumors, suggestive of antigen-exposure; in about half of the cases containing sufficient lymphocytes, we found evidence of exhaustion and a CD8+ TCF7+ phenotype, this latter associated with T-cell reactivation. To the contrary, myelomonocytic cells had case-specific individual combinations of phenotypes and subsets. We identified five distinct monocyte-macrophage cell types: histiocytes, phagocytes, tumor-associated macrophages, inflammatory monocytes and myelomonocytic cells of undefined phenotype. Immunosuppressive molecules (TIM3, B7H3, VISTA, PD1, PDL1) were heterogeneously expressed in inflammatory and endothelial cells. The heterogeneity and phenotype of the monocyte-macrophage population may represents a challenge for which we provide an initial understanding.