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 Regazzi, Phillip Wong, Hikmat Al-Ahmadie, Gopa Iyer, Tripti Tamhane, Amalie Kai Bentzen, Nana Overgaard Herschend, Susan Wolf, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Morten Nielsen, Jonathan E. Rosenberg, Dean F. Bajorin and Sine Reker Hadrup ()
Additional contact information
Jeppe Sejerø Holm: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
Samuel A. Funt: Memorial Sloan Kettering Cancer Center
Annie Borch: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
Kamilla Kjærgaard Munk: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
Anne-Mette Bjerregaard: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
James L. Reading: University College London Cancer Institute
Colleen Maher: Memorial Sloan Kettering Cancer Center
Ashley Regazzi: Memorial Sloan Kettering Cancer Center
Phillip Wong: Memorial Sloan Kettering Cancer Center
Hikmat Al-Ahmadie: Memorial Sloan Kettering Cancer Center
Gopa Iyer: Memorial Sloan Kettering Cancer Center
Tripti Tamhane: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
Amalie Kai Bentzen: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
Nana Overgaard Herschend: Experimental and Translational Immunology, Health Technology, Technical University of Denmark
Susan Wolf: Memorial Sloan Kettering Cancer Center
Alexandra Snyder: Memorial Sloan Kettering Cancer Center
Taha Merghoub: Memorial Sloan Kettering Cancer Center
Jedd D. Wolchok: Memorial Sloan Kettering Cancer Center
Morten Nielsen: Health Technology, Technical University of Denmark
Jonathan E. Rosenberg: Memorial Sloan Kettering Cancer Center
Dean F. Bajorin: Memorial Sloan Kettering Cancer Center
Sine Reker Hadrup: Experimental and Translational Immunology, Health Technology, Technical University of Denmark

Nature Communications, 2022, vol. 13, issue 1, 1-17

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.

Date: 2022
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DOI: 10.1038/s41467-022-29342-0

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