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      Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression

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          Abstract

          Mitochondrial dynamics can regulate Major Histocompatibility Complex (MHC)-I antigen expression by cancer cells and their immunogenicity in mice and in patients with malignancies. A crucial role in the mitochondrial fragmentation connection with immunogenicity is played by the IRE1α-XBP-1s axis. XBP-1s is a transcription factor for aminopeptidase TPP2, which inhibits MHC-I complex cell surface expression likely by degrading tumor antigen peptides. Mitochondrial fission inhibition with Mdivi-1 upregulates MHC-I expression on cancer cells and enhances the efficacy of adoptive T cell therapy in patient-derived tumor models. Therefore mitochondrial fission inhibition might provide an approach to enhance the efficacy of T cell-based immunotherapy.

          Abstract

          Cancer cells downregulate surface expression of major histocompatibility complex I (MHC-I) for immune evasion. Here, the authors show that rapid mitochondrial fission activates the ER-stress response leading to reduced MHC-I complex formation and cell surface expression in solid cancer cells; moreover inhibition of mitochondrial fission increases the immune-mediated anticancer response in murine models.

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          Endoplasmic reticulum stress: cell life and death decisions.

          C. Xu (2005)
          Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
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            Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs

            Key Points Question What is the estimated percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor drugs approved for oncology indications by the US Food and Drug Administration? Findings This cross-sectional study found that the estimated percentage of US patients with cancer who are eligible for checkpoint inhibitor drugs increased from 1.54% in 2011 to 43.63% in 2018. The percentage of patients estimated to respond to checkpoint inhibitor drugs was 0.14% in 2011 and increased to 12.46% in 2018. Meaning The estimated percentages of patients who are eligible for and who respond to checkpoint inhibitor drugs are higher than reported estimates for drugs approved for genome-driven oncology but remain modest.
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              ER tubules mark sites of mitochondrial division.

              Mitochondrial structure and distribution are regulated by division and fusion events. Mitochondrial division is regulated by Dnm1/Drp1, a dynamin-related protein that forms helices around mitochondria to mediate fission. Little is known about what determines sites of mitochondrial fission within the mitochondrial network. The endoplasmic reticulum (ER) and mitochondria exhibit tightly coupled dynamics and have extensive contacts. We tested whether ER plays a role in mitochondrial division. We found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction before Drp1 recruitment. Thus, ER tubules may play an active role in defining the position of mitochondrial division sites.
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                Author and article information

                Contributors
                SFERRONE@mgh.harvard.edu
                fansong2@mail.sysu.edu.cn
                lijins@mail.sysu.edu.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                6 July 2022
                6 July 2022
                2022
                : 13
                : 3882
                Affiliations
                [1 ]GRID grid.412536.7, ISNI 0000 0004 1791 7851, Department of Oral and Maxillofacial Surgery, , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, ; Guangzhou, 510120 China
                [2 ]GRID grid.36425.36, ISNI 0000 0001 2216 9681, Molecular and Cellular Biology, , State University of New York at Stony Brook, ; Stony Brook, NY 11794 USA
                [3 ]GRID grid.412536.7, ISNI 0000 0004 1791 7851, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation of Sun Yat-Sen Memorial Hospital, ; Guangzhou, 510120 China
                [4 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Surgery, , Massachusetts General Hospital, Harvard Medical School, ; Boston, MA 02114 USA
                [5 ]GRID grid.116068.8, ISNI 0000 0001 2341 2786, Massachusetts Institute of Technology, ; Cambridge, MA 02139 USA
                [6 ]GRID grid.411863.9, ISNI 0000 0001 0067 3588, Department of Stomatology, , Longgang District Central Hospital, Affiliated to Guangzhou University of Traditional Chinese Medicine, ; Shenzhen, 518116 China
                [7 ]GRID grid.412536.7, ISNI 0000 0004 1791 7851, Department of Thoracic Surgery, , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, ; Guangzhou, 510120 China
                [8 ]GRID grid.412536.7, ISNI 0000 0004 1791 7851, Cellular Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, ; Guangzhou, 510120 China
                [9 ]GRID grid.412536.7, ISNI 0000 0004 1791 7851, Breast Tumor Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, ; Guangzhou, 510120 China
                [10 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, Department of Neurobiology, , Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, ; Nanjing, 211166 China
                [11 ]GRID grid.260463.5, ISNI 0000 0001 2182 8825, Nanchang Key Laboratory of Cancer Pathogenesis and Translational Research, Center Laboratory, the Third Affiliated Hospital, Nanchang University, ; Nanchang, 330047 China
                [12 ]GRID grid.266539.d, ISNI 0000 0004 1936 8438, Markey Cancer Center, the University of Kentucky, College of Medicine, ; Lexington, KY 40506 USA
                [13 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Chronic Diseases Epidemiology, , Yale University of Public Health, ; New Haven, CT 06520 USA
                [14 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Medical Imaging, , Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, ; Guangzhou, 510060 China
                [15 ]GRID grid.38142.3c, ISNI 000000041936754X, Experimental Therapeutics and Molecular Imaging Lab, Department of Neurology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA 02129 USA
                Author information
                http://orcid.org/0000-0003-3816-1996
                http://orcid.org/0000-0003-2900-8834
                http://orcid.org/0000-0002-6387-9361
                http://orcid.org/0000-0001-6833-5390
                Article
                31417
                10.1038/s41467-022-31417-x
                9259736
                35794100
                3f1fabaa-b775-4378-aac2-37323c17f1b1
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 August 2020
                : 14 June 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);
                Award ID: R01DE028172
                Award ID: R01CA230275
                Award ID: R03CA219603
                Award ID: R03CA253319
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000005, U.S. Department of Defense (United States Department of Defense);
                Award ID: W81XWH-20-1-0315
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: U21A20381
                Award ID: 81872194
                Award ID: 82072990
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation);
                Award ID: 2022B151502006
                Award Recipient :
                Funded by: Guangdong Basic and Applied Basic Research Foundation (Grant No. 2021A1515220138) Guangdong Provincial Science and Technology Project (Grant No: 2021A0505110008)
                Funded by: FundRef https://doi.org/10.13039/501100007162, Guangdong Science and Technology Department (Science and Technology Department, Guangdong Province);
                Award ID: 2114050000501
                Award Recipient :
                Categories
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                © The Author(s) 2022

                Uncategorized
                cancer metabolism,immunosurveillance,energy metabolism
                Uncategorized
                cancer metabolism, immunosurveillance, energy metabolism

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