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Theranostics 2022; 12(13):6038-6056. doi:10.7150/thno.73896 This issue Cite

Research Paper

Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors

Shuting Cao¹, Yu-Wen Hung^1,#, Yi-Chang Wang^1,#, Yiyin Chung^1,#, Yue Qi^1,#, Ching Ouyang², Xiancai Zhong³, Weidong Hu³, Alaysia Coblentz¹, Ellie Maghami⁴, Zuoming Sun^3,5, H. Helen Lin¹, David K. Ann^1,5✉

1. Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
2. Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
3. Department of Immunology and Theranostics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
4. Division of Head and Neck Surgery, City of Hope National Medical Center, Duarte, CA 91010, USA
5. Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
# Equal contribution

✉ Corresponding author: David K. Ann, Ph.D. Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010-3000. Tel: 626-218-6586; E-Mail: dannorg

Abstract

Rationale: Immunosuppression in the tumor microenvironment (TME) is key to the pathogenesis of solid tumors. Tumor cell-intrinsic autophagy is critical for sustaining both tumor cell metabolism and survival. However, the role of autophagy in the host immune system that allows cancer cells to escape immune destruction remains poorly understood. Here, we determined if attenuated host autophagy is sufficient to induce tumor rejection through reinforced adaptive immunity. Furthermore, we determined whether dietary glutamine supplementation, mimicking attenuated host autophagy, is capable of promoting antitumor immunity.

Methods: A syngeneic orthotopic tumor model in Atg5^+/+ and Atg5^flox/flox mice was established to determine the impact of host autophagy on the antitumor effects against mouse malignant salivary gland tumors (MSTs). Multiple cohorts of immunocompetent mice were used for oncoimmunology studies, including inflammatory cytokine levels, macrophage, CD4⁺, and CD8⁺ cells tumor infiltration at 14 days and 28 days after MST inoculation. In vitro differentiation and in vivo dietary glutamine supplementation were used to assess the effects of glutamine on Treg differentiation and tumor expansion.

Results: We showed that mice deficient in the essential autophagy gene, Atg5, rejected orthotopic allografts of isogenic MST cells. An enhanced antitumor immune response evidenced by reduction of both M1 and M2 macrophages, increased infiltration of CD8⁺ T cells, elevated IFN-γ production, as well as decreased inhibitory Tregs within TME and spleens of tumor-bearing Atg5^flox/flox mice. Mechanistically, ATG5 deficiency increased glutamine level in tumors. We further demonstrated that dietary glutamine supplementation partially increased glutamine levels and restored potent antitumor responses in Atg5^+/+ mice.

Conclusions: Dietary glutamine supplementation exposes a previously undefined difference in plasticity between cancer cells, cytotoxic CD8⁺ T cells and Tregs.

Keywords: autophagy, tumor microenvironment, glutamine, CD8, Treg

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