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

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...

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Autores principales: Cao, Shuting, Hung, Yu-Wen, Wang, Yi-Chang, Chung, Yiyin, Qi, Yue, Ouyang, Ching, Zhong, Xiancai, Hu, Weidong, Coblentz, Alaysia, Maghami, Ellie, Sun, Zuoming, Lin, H. Helen, Ann, David K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373812/
https://www.ncbi.nlm.nih.gov/pubmed/35966597
http://dx.doi.org/10.7150/thno.73896
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author Cao, Shuting
Hung, Yu-Wen
Wang, Yi-Chang
Chung, Yiyin
Qi, Yue
Ouyang, Ching
Zhong, Xiancai
Hu, Weidong
Coblentz, Alaysia
Maghami, Ellie
Sun, Zuoming
Lin, H. Helen
Ann, David K.
author_facet Cao, Shuting
Hung, Yu-Wen
Wang, Yi-Chang
Chung, Yiyin
Qi, Yue
Ouyang, Ching
Zhong, Xiancai
Hu, Weidong
Coblentz, Alaysia
Maghami, Ellie
Sun, Zuoming
Lin, H. Helen
Ann, David K.
author_sort Cao, Shuting
collection PubMed
description 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.
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spelling pubmed-93738122022-08-12 Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors Cao, Shuting Hung, Yu-Wen Wang, Yi-Chang Chung, Yiyin Qi, Yue Ouyang, Ching Zhong, Xiancai Hu, Weidong Coblentz, Alaysia Maghami, Ellie Sun, Zuoming Lin, H. Helen Ann, David K. Theranostics Research Paper 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. Ivyspring International Publisher 2022-08-08 /pmc/articles/PMC9373812/ /pubmed/35966597 http://dx.doi.org/10.7150/thno.73896 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Cao, Shuting
Hung, Yu-Wen
Wang, Yi-Chang
Chung, Yiyin
Qi, Yue
Ouyang, Ching
Zhong, Xiancai
Hu, Weidong
Coblentz, Alaysia
Maghami, Ellie
Sun, Zuoming
Lin, H. Helen
Ann, David K.
Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
title Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
title_full Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
title_fullStr Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
title_full_unstemmed Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
title_short Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
title_sort glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373812/
https://www.ncbi.nlm.nih.gov/pubmed/35966597
http://dx.doi.org/10.7150/thno.73896
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