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

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. [Display omitted] •Broad analysis of CD8+ T cell antigen specificity in HBV-HCC patient blood, liver, tumor•Tumor-infiltrating HBV-specific T cells correlate with superior relapse-free survival•Five Trm subsets are enriched in liver- and tumor-infiltrating HBV-specific T cells•HBV-specific Trm cells have expanded TCR clones and lack hallmarks of terminal exhaustion Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Cheng et al. examine the antigen specificities of HCC-infiltrating T cells and reveal that HBV-specific Trm cells are phenotypically distinct, clonally expanded, and are not terminally exhausted, suggesting that these cells may be harnessed for therapeutic purposes.