Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma
Jeppe Sejerø Holm, Samuel A. Funt, Annie Borch, Kamilla Kjærgaard Munk, Anne-Mette Bjerregaard, James L. Reading, Colleen Maher, Ashley Marie Regazzi, Phillip Wong, Hikmat Al‐Ahmadie, Gopa Iyer, Tripti Tamhane, Amalie Kai Bentzen, Nana Overgaard Herschend, Susan De Wolf, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Morten Nielsen, Jonathan E. Rosenberg, Dean F. Bajorin, Sine Reker Hadrup
Abstract
Abstract CD8 + T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8 + T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8 + T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1 + Ki67 + effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8 + T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.