Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma

Yang Cheng, Bavani Gunasegaran, Harsimran D. Singh, Charles-Antoine Dutertre, Chiew Yee Loh, Jia Qi Lim, Jeremy Chase Crawford, Hong Kai Lee, Xiaomeng Zhang, Bernett Lee, Etienne Becht, Wan Jun Lim, Joe Yeong, Chung Yip Chan, Alexander Chung, Brian K. P. Goh, Pierce K. H. Chow, Jerry K. Y. Chan, Florent Ginhoux, David TaiJinmiao Chen, Seng Gee Lim, Weiwei Zhai, Su Pin Choo, Evan W. Newell

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1loTOXlo, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.
Original languageEnglish
Pages (from-to)1825-1840.e7
Number of pages23
JournalImmunity
Volume54
Issue number8
DOIs
Publication statusPublished - 10 Aug 2021
Externally publishedYes

Keywords

  • CD8
  • HBV
  • HCC
  • highly multiplexed pMHC tetramer
  • mass cytometry
  • T cell exhaustion
  • TCR
  • Tex
  • Trm
  • virus-specific T cell

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