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Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

ABSTRACT: CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (T_TS) cells is unclear. We demonstrate that CD4 T_TS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 T_TS cells or exhaustion programming, CD4 T_TS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 T_TS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 T_TS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 T_TS cells for tumor progression and their potential restoration as therapeutic targets.

SUBMITTER: Guo M

PROVIDER: S-EPMC10578141 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

Guo Mengdi M Abd-Rabbo Diala D Bertol Bruna C BC Carew Madeleine M Lukhele Sabelo S Snell Laura M LM Xu Wenxi W Boukhaled Giselle M GM Elsaesser Heidi H Halaby Marie Jo MJ Hirano Naoto N McGaha Tracy L TL Brooks David G DG

Cell reports 20230830 9

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 T< ...[more]

PMID: 37651234

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Project description:Angiogenic and lymphangiogenic remodeling has long been accepted as a hallmark of cancer development and progression; however, the impacts of this remodeling on immunological responses, which are paramount to the responses to immunotherapeutic treatments, are underexplored. As immunotherapies represent one of the most promising new classes of cancer therapy, in this study, we explore the effects of angiogenic and lymphangiogenic normalization on dissemination of molecules injected into the tumor microenvironment to immune cells in lymph nodes draining the tumor as well as in systemically distributed tissues. A system of fluorescent tracers, size-matched to biomolecules of interest, was implemented to track different mechanisms of tumor transport and access to immune cells. This revealed that the presence of a tumor, and either angiogenic or lymphangiogenic remodeling, altered local retention of model biomolecules, trended toward normalizing dissemination to systemic organs, and modified access to lymph node-resident immune cells in manners dependent on mechanism of transport. More specifically, active cell migration by skin-derived antigen presenting cells was enhanced by both the presence of a tumor and lymphangiogenic normalization, while both angiogenic and lymphangiogenic normalization restored patterns of immune cell access to passively draining species. As a whole, this work uncovers the potential ramifications of tumor-induced angiogenesis and lymphangiogenesis, along with impacts of interrogation into these pathways, on access of tumor-derived species to immune cells. Impact Statement Angiogenic and lymphangiogenic normalization strategies have been utilized clinically to interrogate tumor vasculature with some success. In the age of immunotherapy, the impacts of these therapeutic interventions on immune remodeling are unclear. This work utilizes mouse models of angiogenic and lymphangiogenic normalization, along with a system of fluorescently tagged tracers, to uncover the impacts of angiogenesis and lymphangiogenesis on access of tumor-derived species to immune cell subsets within various organs.

Dataset Information

Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

Publications

Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

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