Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Abstract

Summary Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 ( TRAF2 ) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.

Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

“…Third, the limited sample size in our study (only 13 patients received anti-PD-1 antibody therapy) may lead to a bias in the selection of the bTMB cutoff point. Fourth, the difference in the calculation of bTMB between our research (summing all synonymous and nonsynonymous variants) and other studies (summing all nonsynonymous variants) may contribute to a bias in the selection of the bTMB cutoff point (20,21). Finally, our study was a retrospective analysis that may contribute to a statistical discrepancy.…”

A “two-hit” (chemo)therapy to improve checkpoint inhibition in cancer

“…As V and C140 dosages found to significantly improve CI preclinical activity are suitable for a combinatorial use in cancer patients, clinical trials in TNBC and B-cell lymphoma are now planned to confirm the efficacy of this “two-hit” plus CI therapy. It will be of interest to investigate in enrolled patients a number of emerging candidate biomarkers of immune cell activation, including: a) APC activation patterns; b) the generation of new TCF1 + stem-like CD8+ T-cells; c) CXCL13 and CCR5 overexpressing, neo-antigen reactive CD8+ T cells [ 8 ]; d) newly generated IFN-γ–expressing resident memory T cells [ 9 ]; e) pre-treatment values of senescent CD28-CD57+KLGR1+CD8+ T cells [ 10 ]; and f) post-treatment values of proliferating PD-1+CD8+ T cells [ 11 ]. The goal of such a therapy, in fact, is the generation of a long-lasting anti-tumor immunity in treated cancer patients.…”

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

“…Liu et al developed a dynamic matrix-based biomarker that integrates the interferon γ cytokine secretion as a biomarker to predict the immunomodulatory effects of anti-PD-1 antibodies [249]. Litchfield et al performed a pan-tumor analysis to reveal the relative importance of tumor-cell-intrinsic and TME features underpinning ICB responses and resistance [250]. Despite these efforts, it is still challenging to accurately project the effector functions in vivo and the pharmacodynamic responses of immunotherapies.…”