In many solid tumors, the setting of an immunosuppressive environment regulated by macrophages and immune checkpoints (ICP) is often a bad prognosis factor. Thus, targeting this immune environment led to the developments of new immunotherapies that raised high hopes for the treatment of solid tumors. Immunotherapy for chondrosarcoma (CHS) is comparatively less advanced partly because the immune environment of these rare tumors remains sparsely explored. However with their high resistance to conventional therapies CHS are typically tumors for which immunotherapies could be a solution. To get an exhaustive cartography of CHS immune landscape, identify prognosis factors and therapeutic targets, we described the immune populations and immune checkpoints of conventional CHS (CCHS) and dedifferentiated CHS (DD CHS), one of the rarest and most aggressive subtype of CHS.
Immunohistochemical methods (IHC) were used to map the expression of immune cells markers (CD3, CD8, CD68, CD163) on a cohort of 27 CCHS and 49 DD CHS. RT-qPCR was used to screen the expression of a panel of ICP, for the most promising ones, their expression was confirmed by IHC. The impact of the density of Tumor Infiltrating Lymphocytes (TIL), Tumor Associated Macrophages (TAM) and ICP on clinical outcome were analyzed.
TAM were the main immune population encountered in DD and CCHS. Immune infiltrate composition was correlated with DD CHS’ outcome: a high CD68+ TAM density was associated with the presence of metastases at diagnosis (p < 0, 05) and a high CD68+/CD8+ ratio was an independent bad prognosis factor (p < 0.01). PDL1 was expressed in 42.6% of DD CHS while it was absent in CCHS. Of all the ICP tested, CSF1R, B7H3, SIRPA, TIM3 and LAG3 were expressed at mRNA level in both CHS subtypes. The expression of CSF1R by TAM was confirmed by IHC in 62.9% of CCHS and in 89.7% of DD CHS.
By showing that CHS immune environment is mainly composed of macrophages expressing CSF1R and that a high CD68 intratumoral density is correlated with the presence of metastases at diagnosis; our data reinforce the hypothesis of an immunosuppressive environment of this tumor. Our results converge to indicate that an immunomodulation through macrophages could be a promising therapeutic approach for CHS.
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Legal entity responsible for the study
Liddy Shriver; University of Lyon Claude Bernard 1.
All authors have declared no conflicts of interest.