Immune predictors of response to immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer

Abstract

Biomarcador; Inhibidores del punto de control inmunitario; Microambiente tumoral

Biomarcador; Inhibidors del punt de control immunitari; Microambient tumoral

Biomarker; Immune checkpoint inhibitors; Tumor microenvironment

Background Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking. Methods We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis. Results Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3). Conclusions These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.

This research was supported by the Comprehensive Program of Cancer Immunotherapy & Immunology I (CAIMI-I) at the Vall d'Hebron Institute of Oncology, funded by the BBVA Foundation (grant 89/2017). Additional support was provided by the Programme Parrainage Chercheur at Institut Gustave Roussy.