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      Single cell analysis unveils the commonality and heterogeneity between nasopharyngeal and oropharyngeal carcinoma

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          Abstract

          Nasopharyngeal carcinoma (NPC) and oropharyngeal carcinoma (OPC) are subtypes of head and neck cancer with different treatment effects due to the heterogeneity of tumor microenvironments. This study was to investigate the distinctive tumor microenvironments of NPC and OPC. Analyzing single-cell data from 10 cases of each subtype, we reveal significant differences in cellular composition, with NPC microenvironment dominated by T/NK and B cells, and OPC characterized by prevalent epithelial cells and fibroblasts. Dynamic transitions of CD8 T cells are observed in both tumor types, involving shifts from naivety to cytotoxicity, proliferation, and eventual exhaustion/exhausted states. Additionally, Tregs exhibit heightened proliferative abilities in later developmental stages, concomitant with exhaustion. These highly proliferative T cells and Tregs manifest elevated glycolysis and lactate metabolism activities. Furthermore, we explore intercellular communication between glycolytic malignant epithelial cells and these proliferative T cells. These findings offer comprehensive insights into the heterogeneity of tumor microenvironments and provide a solid foundation for future therapeutic strategies and targeted interventions.

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          Influence of tumour micro-environment heterogeneity on therapeutic response.

          Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells. Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment. As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount. The dynamic tumour topography varies drastically even throughout the same lesion. Heterologous cell types within tumours can actively influence therapeutic response and shape resistance.
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            Metabolic support of tumor-infiltrating regulatory T cells by lactic acid

            Regulatory T (T reg ) cells, vital for maintaining immune homeostasis, also represent a major barrier to cancer immunity, as the tumor microenvironment (TME) promotes T reg cell recruitment, differentiation, and activity 1 , 2 . Tumor cells have deregulated metabolism leading to a metabolite-depleted, hypoxic, and acidic TME 3 , placing infiltrating effector T cells in competition with tumors for metabolites, impairing their function 4 – 6 . Conversely, T reg cells maintain high suppressive function within the TME 7 , 8 . As previous studies suggested T reg cells possess a distinct metabolic profile from effector T cells 9 – 11 , we hypothesized the altered metabolic landscape of the TME and increased activity of intratumoral T reg cells are linked. Here we show T reg cells display broad heterogeneity in utilization of glucose metabolism within normal and transformed tissues and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlated with poorer suppressive function and long-term instability, and high glucose culture impaired T reg cell function and stability. T reg cells rather upregulate pathways in metabolism of the glycolytic byproduct lactic acid. T reg cells withstood high lactate conditions, and lactate treatment prevented the destabilizing effects of high glucose, generating intermediates necessary for proliferation. T reg cell-restricted deletion of MCT1, a lactate transporter, revealed lactate uptake is dispensable for peripheral T reg cell function but required intratumorally, resulting in slowed tumor growth and increased response to immunotherapy. Thus T reg cells are metabolically flexible: they can utilize ‘alternative’ metabolites in the TME to maintain suppressive identity. Further, our studies suggest tumors avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.
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              Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments

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                Author and article information

                Contributors
                Journal
                Neoplasia
                Neoplasia
                Neoplasia (New York, N.Y.)
                Neoplasia Press
                1522-8002
                1476-5586
                20 February 2024
                April 2024
                20 February 2024
                : 50
                : 100980
                Affiliations
                [a ]Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
                [b ]Department of Otolaryngology Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China
                [c ]Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China
                Author notes
                [* ]Corresponding author at: Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, PR China. liuguoh@ 123456outlook.com
                [** ]Corresponding author at: Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No.169 Donghu Road, Wuchang District, Wuhan, 430071, PR China. panyunbao@ 123456outlook.com
                [1]

                Equally contribution and co-first authors.

                Article
                S1476-5586(24)00017-4 100980
                10.1016/j.neo.2024.100980
                10891337
                38382442
                de0c4bc0-91ac-4bd8-8114-5ca8b7f500cf
                © 2024 Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 14 November 2023
                : 14 February 2024
                Categories
                Original Research

                nasopharyngeal carcinoma,oropharyngeal carcinoma,tumor microenvironment,cellular heterogeneity,intercellular communication

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