BRCA1 deficiency in mature CD8 T lymphocytes impairs antitumor immunity

Bogang Wu, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Leilei Qi, Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Huai-Chin Chiang, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Haihui Pan, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Xiaowen Zhang, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Alexandra Greenbaum, Ruth Paul Cancer Genetics and Prevention Program, Medical Faculty Associates, The George Washington University, Washington, District of Columbia, USA.
Elizabeth Stark, Ruth Paul Cancer Genetics and Prevention Program, Medical Faculty Associates, The George Washington University, Washington, District of Columbia, USA.
Li-Ju Wang, Department of Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Yidong Chen, Department of Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Bassem R. Haddad, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
Dionyssia Clagett, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
Claudine Isaacs, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
Richard Elledge, San Antonio State Hospital, San Antonio, Texas, USA.
Anelia Horvath, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Yanfen Hu, Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA.
Rong Li, Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, District of Columbia, USA rli69@gwu.edu.

Document Type

Journal Article

Publication Date

2-1-2023

Journal

Journal for immunotherapy of cancer

Volume

11

Issue

2

DOI

10.1136/jitc-2022-005852

Keywords

Adaptive Immunity; Breast Neoplasms; CD8-Positive T-Lymphocytes

Abstract

Women with germline mutations have approximately an 80% lifetime chance of developing breast cancer. While the tumor suppressor function of BRCA1 in breast epithelium has been studied extensively, it is not clear whether deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse knockout (KO) in mature T lymphocytes compromises host antitumor immune response to transplanted syngeneic mouse mammary tumors. T cell adoptive transfer further corroborates CD8 T cell-intrinsic impact of KO on antitumor adaptive immunity. T cell-specific KO mice exhibit fewer total CD8, more exhausted, reduced cytotoxic, and reduced memory tumor-infiltrating T cell populations. Consistent with the preclinical data, cancer-free mutation-carrying women display lower abundance of circulating CD8 lymphocytes than the age-matched control group. Thus, our findings support the notion that deficiency in adaptive immunity could contribute to -related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women.

Department

Biochemistry and Molecular Medicine

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