Peripheral-derived regulatory T cells contribute to tumor-mediated immune suppression in a nonredundant manner

Author:

Hossain Md Moazzem1,King Paul1,Hackett Justin2ORCID,Gerard Herve C.1,Niwinski Rajmund1,Wu Lan3ORCID,Van Kaer Luc3ORCID,Dyson Gregory24,Gibson Heather124ORCID,Borowsky Alexander D.5ORCID,Sebzda Eric14

Affiliation:

1. Department of Biochemistry, Microbiology and Immunology, Wayne State University Medical School, Detroit, MI 48201

2. Department of Oncology, Wayne State University Medical School, Detroit, MI 48201

3. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232

4. Tumor Biology and Microenvironment Research Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201

5. Department of Pathology and Laboratory Medicine, Center for Comparative Medicine, University of California Davis, Davis, CA 95616

Abstract

Identifying tumor-mediated mechanisms that impair immunity is instrumental for the design of new cancer therapies. Regulatory T cells (Tregs) are a key component of cancer-derived immune suppression; however, these lymphocytes are necessary to prevent systemic autoimmunity in mice and humans, and thus, direct targeting of Tregs is not a clinical option for cancer patients. We have previously demonstrated that excising transcription factor Kruppel-like factor 2 ( Klf2 ) within the T cell lineage blocks the generation of peripheral-derived Tregs (pTregs) without impairing production of thymic-derived Tregs. Using this mouse model, we have now demonstrated that eliminating pTregs is sufficient to delay/prevent tumor malignancy without causing autoimmunity. Cancer-bearing mice that expressed KLF2 converted tumor-specific CD4 + T cells into pTregs, which accumulated in secondary lymphoid organs and impaired further T cell effector activity. In contrast, pTreg-deficient mice retained cancer-specific immunity, including improved T cell infiltration into “cold” tumors, reduced T cell exhaustion in tumor beds, restricted generation of tumor-associated myeloid-derived suppressor cells, and the continued production of circulating effector T cells that arose in a cancer-dependent manner. Results indicate that tumor-specific pTregs are critical for early stages of cancer progression and blocking the generation of these inhibitory lymphocytes safely delays/prevents malignancy in preclinical models of melanoma and prostate cancer.

Funder

HHS | NIH | National Cancer Institute

Elsa U. Pardee Foundation

DOD | USA | MEDCOM | CDMRP | DOD Prostate Cancer Research Program

American Cancer Society

Publisher

Proceedings of the National Academy of Sciences

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