Five latent factors underlie response to immunotherapy

Abstract

Response; Immunotherapy

Respuesta; Inmunoterapia

Resposta; Immunoteràpia

Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.

This publication and the underlying study have been made possible partly based on the data that HMF has made available. We also acknowledge the use of data from the INSPIRE clinical trial (NCT02644369) and data obtained from patients presented at the VHIO. N.L.-B. acknowledges funding from the European Research Council (ERC; consolidator grant 682398). This project has received funding from the European Union’s Horizon program HORIZON-HLTH-2021-CARE-05-02 for the project CGI-Clinics under grant agreement no. 101057509. E.B. receives support from Generalitat de Catalunya (2021 SGR 001278) and ERC Advanced Grant 884623. The Institute for Research in Biomedicine Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and an Excellence Institutional grant by the Asociacion Española contra el Cancer and is supported by CERCA (Generalitat de Catalunya).