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

Introduction/Background Although immune checkpoint inhibitors (ICI) have demonstrated their efficacy in endometrial cancer (EC), MMRd/MSI-H and MMRp/MSS tumors present different sensitivity profiles to ICI and some patients present primary resistance. We sought to characterize dissimilarities in the tumor immune microenvironment of MMRd/MSI-H vs MMRp/MSS EC, and to identify mechanisms of resistance. Methodology Patients with EC treated with ICI in 6 French comprehensive care centers were classified as ICI-Responders (R) or Non-Responders (NR) based on best objective response. A multi-immunofluorescence staining (CD20/CD4/CD8/FoxP3/CD68/CK,/DAPI) was performed on sections from archival FFPE primary tumor. Cell densities and spatial proximity were analyzed (inForm software). Presence of T/B lymphoid aggregates (LA)/Tertiary Lymphoid Structures (TLS), microsatellite status, and immune cell densities were correlated to response to ICI. 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 = 0.0165), 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 (p = 0.400). Using a multivariate logistic regression model featuring least absolute shrinkage and selection operator, we found that a low density of CD68+ tumor-associated macrophages (TAMs) in the stroma, was associated with response (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]). Conclusion We showed that MMRd/MSI-H tumors were enriched in LA/TLS and that a low density of TAMs in the stroma was associated with response to ICI enhancing the need to explore TAM-targeted strategies in EC. Disclosures OLS report honoraria from SD, Clovis oncology and GSK and research grants from Astrazeneca. IRC reports receipt of grants/research supports from MSD, Roche and BMS; Research grant/funding (institution) from MSD, Roche, BMS, GSK, Novartis, Astra Zeneca and Merck Sereno; receipt of honoraria or consultation fees from Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis, Abbvie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; Springworks, Adaptimmune, Immunogen, Seagen, Novocure, Daichi Sankyo; Travel support from Roche, AstraZeneca and GSK. RS reports receipt of grants/research supports from Astra-Zeneca; receipt of honoraria or consultation fees from Astra-Zeneca, GSK, Seagen, EISAI, Novartis, Clovis Oncology; non-financial support from MSD, GSK, Novartis. AM reports honoraria from GSK. JSF reports receipt of honoraria or consultation fees from AZ, Daiichi, pfizer, lilly, Novartis, gsk,msd, esai, seagen.