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-1 ^lo TOX ^lo , 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.
Competing Interests: Declaration of interests Y.C. and E.W.N. are inventors on US patent application (pending) held by A(∗)STAR, which includes the uses of tumor-reactive epitope sequences and the epitope-reactive TCRs for treatment against HBV-associated HCC. S.G.L. received research grants from Gilead Science, Merck, and Abbott Diagnostics. S.G.L. served as the advisory board member of Gilead Science, Abbvie, Abbott Diagnostics, Merck, Springbank, and Roche. E.W.N. is the co-founder, shareholder, and an advisor and is on the board of directors of ImmunoScape Pte. Ltd. and is an advisor for Neogene Therapeutics and Nanostring Technologies. P.K.H.C. has received honoraria from Sirtex Medical, Ipsen, Bristol Myers Squibb, Oncosoil, Bayer, Roche, New B Innovation, MSD, EISA, Abbott, IQVIA, Genetech, L.E.K. Consulting, and AstraZeneca in an advisory role.
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