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

Immunity. 2021 Aug 10;54(8):1825-1840.e7. doi: 10.1016/j.immuni.2021.06.013. | PubMed

Yang Cheng¹, Bavani Gunasegaran¹, Harsimran D Singh¹, Charles-Antoine Dutertre², Chiew Yee Loh¹, Jia Qi Lim³, Jeremy Chase Crawford⁴, Hong Kai Lee¹, Xiaomeng Zhang¹, Bernett Lee¹, Etienne Becht⁵, Wan Jun Lim⁶, Joe Yeong⁷, Chung Yip Chan⁸, Alexander Chung⁸, Brian K P Goh⁸, Pierce K H Chow⁹, Jerry K Y Chan¹⁰, Florent Ginhoux¹, David Tai¹¹, Jinmiao Chen¹, Seng Gee Lim¹², Weiwei Zhai¹³, Su Pin Choo⁶, Evan W Newell¹⁴

1. Singapore Immunology Network, A(∗)STAR, 8A Biomedical Grove, Singapore 138648, Singapore.
2. Singapore Immunology Network, A(∗)STAR, 8A Biomedical Grove, Singapore 138648, Singapore; Emerging Infectious Disease Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Inserm U1015, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94800 Villejuif, France.
3. Genome Institute of Singapore, A(∗)STAR, 60 Biopolis Street, Singapore 138672, Singapore.
4. Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
5. Singapore Immunology Network, A(∗)STAR, 8A Biomedical Grove, Singapore 138648, Singapore; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA.
6. Division of Medical Oncology, National Cancer Center Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
7. Singapore Immunology Network, A(∗)STAR, 8A Biomedical Grove, Singapore 138648, Singapore; Division of Pathology, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore.
8. Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore; Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
9. Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore; Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Division of Surgery and Surgical Oncology, National Cancer Center Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
10. Department of Reproductive Medicine, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore; Obstetrics and Gynaecology Academic Clinical Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
11. Division of Medical Oncology, National Cancer Center Singapore, 11 Hospital Drive, Singapore 169610, Singapore; Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
12. Division of Gastroenterology and Hepatology, National University Health System, 1E Kent Ridge Road, Singapore 119228, Singapore.
13. Genome Institute of Singapore, A(∗)STAR, 60 Biopolis Street, Singapore 138672, Singapore; Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
14. Singapore Immunology Network, A(∗)STAR, 8A Biomedical Grove, Singapore 138648, Singapore; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA. Electronic address: enewell@fredhutch.org.

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.

Presented By Yang Cheng | ORCID iD