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Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8⁺ T cells via ME1 up-regulation.

ABSTRACT: Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8⁺ T cells. We have termed the rebound of cytotoxic CD8⁺ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1⁺ CD8⁺ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8⁺ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency.

SUBMITTER: Gicobi JK

PROVIDER: S-EPMC10651128 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 up-regulation.

Gicobi Joanina K JK Mao Zhiming Z DeFranco Grace G Hirdler Jacob B JB Li Ying Y Vianzon Vianca V VV Dellacecca Emilia R ER Hsu Michelle A MA Barham Whitney W Yan Yiyi Y Mansfield Aaron S AS Lin Yi Y Wu Xiaosheng X Hitosugi Taro T Owen Dawn D Grams Michael P MP Orme Jacob J JJ Lucien Fabrice F Zeng Hu H Park Sean S SS Dong Haidong H

Science advances 20231115 46

Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8+ T cells. We have termed the rebound of cytotoxic CD8+ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms ...[more]

PMID: 37967193

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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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Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8⁺ T cells via ME1 up-regulation.

Publications

Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8<sup>+</sup> T cells via ME1 up-regulation.

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