Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers

Rami Yossef; Sri Krishna; Sivasish Sindiri; Frank J Lowery; Amy R Copeland; Jared J Gartner; Maria R Parkhurst; Neilesh B Parikh; Kyle J Hitscherich; Shoshana T Levi; Praveen D Chatani; Nikolaos Zacharakis; Noam Levin; Nolan R Vale; Shirley K Nah; Aaron Dinerman; Victoria K Hill; Satyajit Ray; Alakesh Bera; Lior Levy; Li Jia; Michael C Kelly; Stephanie L Goff; Paul F Robbins; Steven A Rosenberg

doi:10.1016/j.ccell.2023.11.005

Phenotypic signatures of circulating neoantigen-reactive CD8⁺ T cells in patients with metastatic cancers

Cancer Cell. 2023 Dec 11;41(12):2154-2165.e5. doi: 10.1016/j.ccell.2023.11.005. Epub 2023 Nov 30.

Authors

Rami Yossef¹, Sri Krishna², Sivasish Sindiri³, Frank J Lowery³, Amy R Copeland³, Jared J Gartner³, Maria R Parkhurst³, Neilesh B Parikh³, Kyle J Hitscherich³, Shoshana T Levi³, Praveen D Chatani³, Nikolaos Zacharakis³, Noam Levin³, Nolan R Vale³, Shirley K Nah³, Aaron Dinerman³, Victoria K Hill³, Satyajit Ray³, Alakesh Bera³, Lior Levy³, Li Jia⁴, Michael C Kelly⁵, Stephanie L Goff³, Paul F Robbins³, Steven A Rosenberg⁶

Affiliations

¹ Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: yosef.rami@gmail.com.
² Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: sri.krishna@nih.gov.
³ Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ National Institutes of Health Library, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory, Bethesda, MD 20892, USA.
⁶ Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: sar@nih.gov.

PMID: 38039963
PMCID: PMC10843665 (available on 2024-12-11)
DOI: 10.1016/j.ccell.2023.11.005

Abstract

Circulating T cells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor T cells. By single-cell transcriptomic profiling of 36 neoantigen-specific T cell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8⁺ T cells (NeoTCR_PBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific T cells revealed that NeoTCR_PBL T cells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCR_PBL populations target the same neoantigens as TILs. However, NeoTCR_PBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCR_PBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCR_PBL signature provides an alternative source for identifying antitumor T cells from PBL of cancer patients, enabling immune monitoring and immunotherapies.

Keywords: CD8(+) T cells; T cell receptors; adoptive cell transfer; blood; neoantigens.

MeSH terms

Antigens, Neoplasm
CD8-Positive T-Lymphocytes*
Humans
Lymphocytes, Tumor-Infiltrating
Neoplasms* / genetics
Neoplasms* / metabolism
Neoplasms* / therapy
Prospective Studies
Receptors, Antigen, T-Cell

Substances

Antigens, Neoplasm
Receptors, Antigen, T-Cell

Abstract

MeSH terms

Substances

Grants and funding