The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

Andrew Chow, Fathema Z. Uddin, Michael Liu, Anton Dobrin, Barzin Y. Nabet, Levi Mangarin, Yonit Lavin, Hira Rizvi, Sam E. Tischfield, Alvaro Quintanal-Villalonga, Joseph M. Chan, Nisargbhai Shah, Viola Allaj, Parvathy Manoj, Marissa Mattar, Maximiliano Meneses, Rebecca Landau, Mariana Ward, Amanda Kulick, Charlene KwongMatthew Wierzbicki, Jessica Yavner, Jacklynn Egger, Shweta S. Chavan, Abigail Farillas, Aliya Holland, Harsha Sridhar, Metamia Ciampricotti, Daniel Hirschhorn, Xiangnan Guan, Allison L. Richards, Glenn Heller, Jorge Mansilla-Soto, Michel Sadelain, Christopher A. Klebanoff, Matthew D. Hellmann, Triparna Sen, Elisa de Stanchina, Jedd D. Wolchok, Taha Merghoub, Charles M. Rudin

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.

Original languageEnglish
Pages (from-to)93-106.e6
JournalImmunity
Volume56
Issue number1
DOIs
StatePublished - 10 Jan 2023
Externally publishedYes

Keywords

  • CD8 T cells
  • T cell receptors
  • immune checkpoint blockade
  • non-small cell lung cancer
  • tumor mutation burden

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