Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma
Open accessAbstract
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.
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In HBV-associated TME, effector CD8+ T cells undergo function evolution, correlating with improved survival in advanced HCC.
“At the single-cell level, studies have shown that in HBV-associated TME, effector CD8 + T cells undergo function evolution, correlating with improved survival in advanced HCC.”
From Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors (2025) · cites this paper as [104]
Enrichment and activation of HBV-specific tissue-resident memory CD8+ T cells are critical mechanisms for effective immunotherapy in HCC.
“Enrichment and activation of HBV-specific tissue-resident memory CD8 + T cells have also been identified as critical mechanisms for effective immunotherapy in HCC104.”
From Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors (2025) · cites this paper as [104]
Cytotoxic HBV-specific T cells are found in HBV+ HCC tumors.
“While cytotoxic HBV-specific T cells are found in HBV+ HCC tumors”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [36]
Thirty-one HBV peptides restricted to HLA-A*02 or HLA-A*02:01 and reported to induce CD8+ T cell responses were included in this study.
“A total of thirty-one HBV peptides that were restricted to HLA-A∗02 or HLA-A∗02:01 and reported to induce CD8+ T cell response36”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [36]
Three genes, including CCL4L2, NR4A2, and CCL4, consistently ranked among the top three most differentially expressed genes in both datasets.
“Three genes, including CCL4L2, NR4A2, and CCL4,consistently ranked among the top three most differentially expressed genes in both datasets.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [36]
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Self-citationMicrobiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors
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“…HBV-associated TME, effector CD8 + T cells undergo function evolution, correlating with improved survival in advanced HCC. Enrichment and activation of HBV-speci fi c tissue-resident memory CD8 + T cells have also been identi fi ed as critical mechanisms for effective immunotherapy in HCC 104 .”
InfluentialLiver-resident memory T cells: life in lockdown
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- Authors
- Cheng, Y., Gunasegaran, B., Singh, H. D., Dutertre, C.-A., Loh, C. Y., Lim, J. Q., Crawford, J. C., Lee, H. K., Zhang, X., Lee, B., Becht, E., Lim, W. J., Yeong, J., Chan, C. Y., Chung, A., Goh, B. K. P., Chow, P. K. H., Chan, J. K. Y., Ginhoux, F., Tai, D., Chen, J., Lim, S. G., Zhai, W., Choo, S. P., & Newell, E. W.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Inserm (FR)
- St. Jude Children's Research Hospital (US)
- National Cancer Centre Singapore (SG)
- SingHealth (SG)
- National University of Singapore (SG)
- National University Health System (SG)
- Singapore Immunology Network (SG)
- Corresponding author
- Newell, Evan W.
- ORCID
- Cheng, Yang
- Gunasegaran, Bavani
- Dutertre, Charles-Antoine
- Crawford, Jeremy Chase
- Lee, Hong Kai
- Zhang, Xiaomeng
- Lee, Bernett
- Lim, Wan Jun
- Yeong, Joe
- Chan, Chung Yip
- Chung, Alexander
- Goh, Brian K.P.
- Chow, Pierce K.H.
- Chan, Jerry K.Y.
- Ginhoux, Florent
- Tai, David
- Chen, Jinmiao
- Lim, Seng Gee
- Zhai, Weiwei
- Choo, Su Pin
- Newell, Evan W.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 54
- Issue
- 8
- Pages
- 1825-1840.e7
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W3180432427
- Cited by
- 142
- References
- 12
- Citations by year
- 2026: 25 · 2025: 29 · 2024: 26 · 2023: 31 · 2022: 23 · 2021: 8
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- hepatocellular carcinoma, hepatitis B virus, tumor-infiltrating lymphocytes, tissue-resident memory T cells, CD8+ T cells, T cell exhaustion, PD-1, TOX, HBV-specific T cell responses, neoantigens, relapse-free survival, chronic hepatitis B, immune checkpoint blockade, peptide-MHC tetramers, high-dimensional analysis
- MeSH terms
- Antigens, Neoplasm, Hepatitis B virus, Carcinoma, Hepatocellular, High Mobility Group Proteins, Humans, Immunologic Memory, Liver Neoplasms, Neoplasm Recurrence, Local, Tumor Cells, Cultured, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Hepatitis B, Chronic, Programmed Cell Death 1 Receptor
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