Mechanisms underlying responsiveness and resistance to cancer immunotherapy

Abstract

Immunotherapies, including anti-PD-1 immune checkpoint blockade therapy, offer hopes for end-stage cancer patients, yet with limited response rates among the patients. It is thus important to understand the mechanisms underlying responsiveness and resistance to cancer immunotherapy. CD8+ T cells are the main mediators in tumor immunity and cancer immunotherapy. T cells differentiate into effector cells during pathogen infections, but become “exhausted” in the tumor microenvironments. A stem-like population, namely progenitor of exhausted T cells (Tpex), has been recently identified, which can terminally develop into effector T cells, which ultimately get “exhausted”. Tpex are also the main responder in anti-PD-1 immune checkpoint therapy. Combination of anti-PD-1 with lenvatinib showed improved clinical efficacy in multiple cancers, yet the underlying immunological mechanisms are largely unclear. Recently, we have analyzed the transcriptional mechanisms underlying maintenance and differentiation of Tpex in cancer. Moreover, we compared T cells in hepatocellular carcinoma (HCC) patients before and after combination treatment using single-cell transcriptomics and TCR clonotype analyses. This work revealed additional T cell subsets associated with clinical benefits and resistance in cancer immunotherapy. Our work may benefit further improvements in cancer immunotherapy.