1. Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells.
- Author
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Manukian G, Kivolowitz C, DeAngelis T, Shastri AA, Savage JE, Camphausen K, Rodeck U, Zarif JC, and Simone NL
- Subjects
- Adult, Aged, Animals, CD4-Positive T-Lymphocytes chemistry, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes radiation effects, CD8-Positive T-Lymphocytes chemistry, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes radiation effects, Combined Modality Therapy methods, Disease Progression, Female, Flow Cytometry, Forkhead Transcription Factors, Humans, Interleukin Receptor Common gamma Subunit blood, Interleukin-10 Receptor beta Subunit blood, Interleukin-2 Receptor alpha Subunit, Lymphocyte Depletion methods, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mice, Inbred BALB C, Middle Aged, Programmed Cell Death 1 Receptor metabolism, Random Allocation, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, Transforming Growth Factor beta2 blood, Transforming Growth Factor beta3 blood, Triple Negative Breast Neoplasms blood, Triple Negative Breast Neoplasms immunology, Triple Negative Breast Neoplasms mortality, Tumor Microenvironment immunology, Caloric Restriction, Lymphocytes, Tumor-Infiltrating radiation effects, T-Lymphocytes, Regulatory radiation effects, Triple Negative Breast Neoplasms radiotherapy, Tumor Microenvironment radiation effects
- Abstract
Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8
+ tumor infiltrating lymphocytes (TIL) to augment antitumor immunity. Radiation (RT) can promote immunogenic cell death with increased antitumor T cell activity but also stimulates suppressive regulatory T cells (Tregs). Because metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, we treated mice with ad libitum (AL) diet, radiation, a CR diet, or CR + RT, and demonstrated an immune suppressive environment with a significant increase in CD4+ CD25+ Foxp3+ Tregs after RT but not in CR-fed mice. CD8:Treg ratio in CR + RT TIL increased 4-fold compared with AL + RT mice. In vivo CD8 depletion was performed to assess the role of effector T cells in mitigating the effects of CR, and it was found that in mice undergoing CR, depletion of CD8 T cells resulted in increased tumor progression and decreased median survival compared with isotype control-treated mice. In addition, PD-1 expression on CD3+ CD8+ T cells within the tumor microenvironment was significantly increased in CR + RT versus AL + RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and postintervention, and a cytokine array demonstrated that patients treated with CR + RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rβ, and TGF-β2 and 3 compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg, and increases PD-1 expression via a process dependent on CD8 T cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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