Through multi-omic analysis of multi-region and longitudinal tumor biopsies taken pre- and post-treatment from 15 patients (5 responders) with ccRCC, Au et al. evaluated genomic and TME features associated with responsiveness to anti-PD-1. Responders had more similarity in TCR repertoire between timepoints and heightened expansion, indicating a greater degree of maintenance of pre-existing, tumor-specific intratumoral T cells than non-responders. Neither TMB nor expansion of novel T cell clones correlated with response. Expression of CD3E, CD8A, GZMB, and TCF7 were higher, and pathways of immune-activation and TCR signaling were enriched in responders.
Contributed by Margot O’Toole
ABSTRACT: ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.