Immune landscape and TAM density in endometrial cancer: implications for immune checkpoint inhibitors efficacy

Abstract

Abstract Background Although immune checkpoint inhibitors (ICI) have demonstrated their efficacy in endometrial cancer (EC), mismatch repair deficient/microsatellite instability high (MMRd/MSI-H) and mismatch repair proficient/ microsatellite stable (MMRp/MSS) tumors present different sensitivity profiles to ICI. Moreover, a third of patients with MMRd/MSI-H tumors present primary resistance to ICI alone. We aimed to characterize dissimilarities in the tumor immune microenvironment of ICI-treated MMRd/MSI-H vs MMRp/MSS EC, and to identify possible mechanisms of resistance. Methods EC patients treated with ICI in 6 French comprehensive cancer centers were identified and classified as ICI-Responders or Non-Responders based on best objective response. A seven-color multi-immunofluorescence staining (CD20, CD4, CD8, FoxP3, CD68, CK, DAPI) was performed on sections from archival formalin-fixed paraffin-embedded primary tumors. Cell densities and spatial proximity were analyzed using inForm software. T/B lymphoid aggregates (LA) and Tertiary Lymphoid Structures (TLS) were separately quantified. Microsatellite status, presence of LA/TLS and immune cell densities were correlated to response to treatment. Results Twenty-one MMRd/MSI-H and 12 MMRp/MSS tumors were analyzed. We observed more MMRd/MSI-H tumors with LA/TLS compared to MMRp/MSS cases: 81% vs 17%, p = < 0.001. There were more CD8 + T effector cells in the vicinity of B cells in MMRd/MSI-H tumors compared to MMRp/MSS tumors (1.26 [0-3.40] vs 0.49 [0-1.86], p = 0.017), suggesting cooperation between effector T cells and B cells in MMRd/MSI-H tumors. No differences were shown in terms of the presence of LA/TLS and the subsequent response to ICI in EC (p = 0.400). Using a multivariate logistic regression model, we found that a low density of CD68+ tumor-associated macrophages (TAMs) in the stroma, was associated with response to ICI in EC (Odds Ratio (OR) = 11.67, CI95 [1.69-237.45], p = 0.033) and showed good accuracy in predicting response to ICI in the whole cohort (AUC = 0.75, 95% CI [0.59–0.91]). Conclusions We provide a comprehensive characterization of the immune landscape in EC patients treated with ICIs. The distinct immune infiltrate patterns observed in MMRd/MSI-H and MMRp/MSS tumors, coupled with the significant negative association between TAM density and ICI response, underscore the potential of immune components as predictive biomarkers.