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SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8⁺ T cell cytotoxic function.

ABSTRACT: Transforming growth factor-β is well known to restrain cytotoxic T cell responses to maintain self-tolerance and to promote tumor immune evasion. In this study, we have investigated the role of SMAD4, a core component in the TGF-β signaling pathway, in CD8⁺ T cells. Unexpectedly, we found that SMAD4 was critical in promoting CD8⁺ T cell function in both tumor and infection models. SMAD4-mediated transcriptional regulation of CD8⁺ T cell activation and cytotoxicity was dependent on the T cell receptor (TCR) but not TGF-β signaling pathway. Following TCR activation, SMAD4 translocated into the nucleus, up-regulated genes encoding TCR signaling components and cytotoxic molecules in CD8⁺ T cells and thus reinforced T cell function. Biochemically, SMAD4 was directly phosphorylated by ERK at Ser³⁶⁷ residue following TCR activation. Our study thus demonstrates a critical yet unexpected role of SMAD4 in promoting CD8⁺ T cell-mediated cytotoxic immunity.

SUBMITTER: Liu X

PROVIDER: S-EPMC9328680 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8+ T cell cytotoxic function.

Liu Xinwei X Hao Jing J Wei Peng P Zhao Xiaohong X Lan Qiuyan Q Ni Lu L Chen Yongzhen Y Bai Xue X Ni Ling L Dong Chen C

Science advances 20220727 30

Transforming growth factor-β is well known to restrain cytotoxic T cell responses to maintain self-tolerance and to promote tumor immune evasion. In this study, we have investigated the role of SMAD4, a core component in the TGF-β signaling pathway, in CD8+ T cells. Unexpectedly, we found that SMAD4 was critical in promoting CD8+ T cell function in both tumor and infection models. SMAD4-mediated transcriptional regulation of CD8+ T cell activation and cytotoxicit ...[more]

PMID: 35895826

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Project description:PurposeImmune checkpoint inhibitors have recently been approved by the US FDA as first and/or second line therapy in a subset of cancer types. Recent evidence suggests that the quantity of tumor infiltrating lymphocytes (TILs) influences the likelihood of response to immune checkpoint inhibitors. Here, we set out to assess the density of CD8+ lymphocytes in a wide range of different cancer types and subtypes.MethodsThe density of CD8+ lymphocytes was compared across different cancer types using tissue microarrays (TMAs) composed of up to 50 tumor samples each from 84 different cancer types and subtypes. In total 2652 cancers and 608 normal tissues were successfully analyzed by CD8 immunohistochemistry followed by automated image analysis of digitized slides.ResultsWe found that the median CD8+ lymphocyte counts ranged from 6 cells/mm2 in pleomorphic adenoma up to 1573 cells/mm2 in Hodgkin's lymphoma. The CD8 counts were generally lower in normal tissues compared to cancer tissues. Blood vessels of the spleen were the only non-lymphatic tissue staining positive for CD8. Tumor types approved for checkpoint inhibitor therapy, including malignant melanoma (81), muscle invasive urothelial carcinoma (119), small cell lung cancer (120), clear cell renal cell cancer (153), squamous cell carcinoma (189) and adenocarcinoma of the lung (328) as well as Hodgkin's lymphoma (1573) were all ranking among the upper half of our list. Comparably high CD8 densities (median cells/mm2) were also found in several rare and aggressive cancer types including Merkel cell carcinoma (70), angiosarcoma (95), anaplastic thyroid cancer (156) and embryonal carcinoma of the testis (186). In 73 of the 84 analyzed cancer types, the highly variable CD8 counts occasionally exceeded the average CD8 count of tumors for which checkpoint inhibitors have been approved.ConclusionThese data support the concept that among most tumor types at least some individual cancers may benefit from treatment with immune checkpoint inhibitors.

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SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8⁺ T cell cytotoxic function.

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SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8<sup>+</sup> T cell cytotoxic function.

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Dataset Information

SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8+ T cell cytotoxic function.

Publications

SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8&lt;sup&gt;+&lt;/sup&gt; T cell cytotoxic function.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8⁺ T cell cytotoxic function.

SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8<sup>+</sup> T cell cytotoxic function.