The immune landscape of chondrosarcoma - potential for therapeutic targeting of CSFR1+ macrophages

Survival rate for Chondrosarcoma (CHS) is at a standstill, more effective treatments are urgently needed. Consequently, a better understanding of CHS biology and its immune environment is crucial to identify new prognostic factors and therapeutic targets. Here, we exhaustively describe the immune landscape of conventional and dedifferentiated CHS. Using IHC and molecular analyses (RT-qPCR), we mapped the expression of immune cell markers (CD3, CD8, CD68, CD163) and immune checkpoints (ICPs) from a cohort of 27 conventional and 49 dedifferentiated CHS. The impact of the density of tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs) and immune checkpoints (ICPs) on clinical outcome were analyzed. We reveal that TAMs are the main immune population in CHS. Focusing on dedifferentiated CHS, we found that immune infiltrate composition is correlated with patient outcome, a high CD68+/CD8+ ratio being an independent poor prognostic factor (p < 0.01), and high CD68+ levels being associated with the presence of metastases at diagnosis (p < 0.05). Among the ICPs evaluated, CSF1R, B7H3, SIRPA, TIM3 and LAG3 were expressed at the mRNA level in both CHS subtypes. Furthermore, PDL1 expression was confirmed by IHC exclusively in dedifferentiated CHS (42.6% of the patients) and CSF1R was expressed by TAMs in 89.7% of dedifferentiated CHS (vs 62.9% in conventional). Our results show that the immune infiltrate of CHS is mainly composed of immunosuppressive actors favoring tumor progression. Our results indicate that dedifferentiated CHS could be eligible for anti-PDL1 therapy and more importantly immunomodulation through CSF1R + macrophages could be a promising therapeutic approach for both CHS subtypes.