HBV-Specific T_rm Cells Correlate with Relapse-Free Survival in HCC

Chronic hepatitis B virus (HBV) infection often leads to hepatocellular carcinoma (HCC), and studies have suggested that inefficient T-cell responses to HBV observed in patients with HCC may result from T-cell exhaustion. However, the role of exhausted T cells in the immune response to HCC is not well understood, as other studies have found that HBV-specific T cells from patients at different stages of HBV infection did not display phenotypes consistent with exhaustion. To investigate characteristics of HCC-infiltrating T-cells, Cheng and colleagues assessed the antigen specificity of CD8⁺ T cells from peripheral blood mononuclear cells, histologically healthy liver, and HCC lesions of 46 patients by screening a library of peptide–MHC tetramers, representing epitopes derived from tumor antigens, HBV, and other unrelated viruses, as well as personalized neoantigens. Whereas 91 different antigen-specific CD8⁺ T-cell populations were identified across patient samples, HBV-specific CD8⁺ T cells were abundant in liver and HCC lesions. In samples from patients with underlying HBV infection (n = 30/46), the presence of intrahepatic HBV-specific CD8⁺ T-cell populations correlated with improved patient relapse-free survival. Dimensionality reduction and clustering analysis revealed five intrahepatic PD-1⁺ populations that resembled tissue-resident memory T (T_rm) cells, two of which were CD103⁺ T_rm subsets that enriched for non–terminally exhausted intratumoral and intrahepatic HBV-specific CD8⁺ T cells. Moreover, single-cell RNA-sequencing analysis found that the majority of intratumoral and intrahepatic HBV-specific CD8⁺ T cells belonged to two clusters that not only displayed minimal expression of TOX and TCF7, critical genes in T-cell exhaustion development, but also did not significantly resemble the transcriptional profiles of terminally exhausted T cells. Instead, these HBV-specific CD8⁺ T cells expressed genes important in T_rm cell development. In addition to evidence suggesting functional T-cell activity, most HBV-specific T-cell receptors were clonally expanded. In summary, this work comprehensively characterizes infiltrating CD8⁺ T-cell populations in patients with HCC and highlights the therapeutic potential of HBV-specific T_rm cells in enhancing an antitumor immune response.

Cheng Y, Gunasegaran B, Singh HD, Dutertre C-A, Loh CY, Lim JQ, et al. Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma. Immunity 2021 Jul 15 [Epub ahead of print].

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