Five latent factors underlie response to immunotherapy

Usset, Joseph; Rosendahl Huber, Axel; Andrianova, Maria A.; Batlle Gómez, Eduard; Carles, Joan; Cuppen, Edwin; Elez, Elena; Felip, Enriqueta; Gómez Rey, Marina; Lo Giacco, Deborah; Martínez Jiménez, Francisco; Muñoz Couselo, Eva; Siu, Lillian L.; Tabernero Cartula, Josep; Vivancos Prellezo, Ana; Muiños, Ferran; Gonzalez-Perez, Abel; López Bigas, Núria

doi:http://dx.doi.org/10.1038/s41588-024-01899-0

Five latent factors underlie response to immunotherapy

Citation

Usset J, Rosendahl Huber A, Andrianova MA, Batlle E, Carles J, Cuppen E, et al. Five latent factors underlie response to immunotherapy. Nat Genet. 2024 Oct;56(10):2112-20. DOI: 10.1038/s41588-024-01899-0

Abstract

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.