Transforming Growth Factor-β Signaling in Immunity and Cancer

Batlle, Eduard; Massagué, Joan

doi:10.1016/j.immuni.2019.03.024

Cited by 1,459 publications

(1,351 citation statements)

References 189 publications

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“…Genes regulated by Yap include several key effectors of T cell activation, including those controlling JAK-STAT signaling that modulate the polarization of naïve CD4s into T helper subsets (Seif et al, 2017). Notably, Yapregulated genes are also enriched for those regulated by the TGFb and Wnt pathways, which have important pleotropic roles in T cell biology (Batlle and Massague, 2019;Chae and Bothwell, 2018). Given the known convergence of Yap with these immunomodulatory pathways (Varelas and Wrana, 2012) it is likely Yap directs their transcriptional targets and signal strength.…”

Section: Discussionmentioning

confidence: 99%

Yap suppresses T cell function and infiltration in the tumor microenvironment

Stampouloglou

Federico

Slaby

et al. 2019

Preprint

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A major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon CD4 + and CD8 + T cell activation and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicatesYap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

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Section: Discussionmentioning

confidence: 99%

Yap suppresses T cell function and infiltration in the tumor microenvironment

Stampouloglou

Federico

Slaby

et al. 2019

Preprint

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“…Chemokines through their G proteincoupled receptors (GPCRs) are major drivers of T-cell chemotaxis and trafficking and keep attracting interest as potential therapeutic targets in immuno-oncology (Chow and Luster, 2014;Do et al, 2020;Vilgelm and Richmond, 2019). Tumors evolve various strategies to evade T-cell infiltration via activation of oncogenic signaling pathways, for instance by suppressing chemokine production and signaling and/or by secreting antimigratory molecules such as Wnt ligands and TGF (Batlle and Massague, 2019;Hinshaw and Shevde, 2019;Kerdidani et al, 2019;Spranger et al, 2015). Yet, much remains to be learned about soluble factors and GPCR ligands that counteract T-cell chemotaxis and tumor infiltration.…”

Section: Introductionmentioning

confidence: 99%

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

Matas-Rico

Àvila

Zon

et al. 2020

Preprint

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To improve immunotherapy efficacy, a better understanding of the factors that regulate Tcell migration into tumors is essential. Here we uncover a role for autotaxin (ATX) in this process. ATX (encoded by ENPP2) produces lysophosphatidic acid (LPA) that activates G protein-coupled receptors (LPAR1-6) to regulate multiple (patho)physiological processes, including tumor progression via LPAR1 and lymphocyte homing via LPAR2.Unexpectedly, we find that melanoma cell-secreted ATX is a major chemorepellent for tumor-infiltrating lymphocytes ex vivo through Gα12/13-coupled LPAR6, with ATX functioning as an LPA-producing chaperone. Using an anti-cancer vaccination model, we provide proof-of-concept that secreted ATX opposes tumor infiltration of CD8+ T cells.Additionally, ENPP2 expression in melanoma tumors correlates with reduced CD8+ T-cell infiltration as inferred from single-cell transcriptomics. Hence, by counteracting T-cell infiltration while activating tumor cells via different LPA receptors, the ATX/LPA complex exerts dual actions in the tumor immune microenvironment, which may provide new therapeutic approaches.

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“…As an ancestral cell growth factor family member, TGF exerts pleiotropic regulatory functions on numerous pathophysiological processes including carcinogenesis and immune responses 14,15,35,36 . In transplantation models of cancer, TGF suppression of tumor immunity has been attributed to the inhibition of tumor-reactive CTLs 20,21,37,38 .…”

Section: Discussionmentioning

confidence: 99%

TGFβ Suppresses Type 2 Immunity to Cancer

Liu

Kuo

Capistrano

et al. 2020

Preprint

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The immune system employs two distinct defense strategies against infections: pathogen elimination typified by type 1 immunity, and pathogen containment exemplified by type 2 immunity in association with tissue repair. Akin to infectious diseases, cancer progresses with cancer cell acquisition of microorganism-like behavior propagating at the expense of the host.While immunological mechanisms of cancer cell elimination are well defined, whether immunemediated cancer cell containment can be induced is poorly understood. Here we show that ablation of transforming growth factor-β receptor II (TGFβRII) in CD4 + T cells promotes tumor tissue healing and halts cancer progression. Notably, the restorative response is dependent on the T helper 2 cytokine IL-4 fortifying vasculature organization that spares only proximal layers of cancer cells from hypoxia, nutrient starvation and death. Thus, type 2 immunity represents an effective cancer defense mechanism, and TGFβ signaling in helper T cells may be targeted for novel cancer immunotherapy.3 TextIn response to invading pathogens, vertebrate immune system employs two discrete strategies of host defense: pathogen elimination typified by type 1 immunity following innate immune recognition of prokaryotic microorganisms 1 , and pathogen containment associated with tissue repair manifested by type 2 immunity following the invasion of metazoan parasites that inflict tissue damage 2 . Similar to infectious diseases, cancer imposes insults to the host with cancer cell acquisition of microorganism-like behavior of clonal expansion. Indeed, cancer cell-targeted type 1 immunity mediated by CD8 + cytotoxic T lymphocytes (CTLs), cytotoxic innate lymphocytes and innate-like T cells represent host protective mechanisms of cancer cell elimination 3-5 . Notwithstanding, the host impact of cancer cells is much more intimate than that of microbes, and cancer pathogenicity, in particular that of solid tumors, is dependent on cancer cell coercing a supportive environment that promotes tumor encroachments leading to the impairment of tissue function [6][7][8][9] . Notably, tumor tissues resemble active wounds, and are considered as "wounds that do not heal" 10 , implying that cancer microenvironment-targeted tissue repair responses could restrain tumor progression.Dissimilar from infectious diseases, cancer arises from malignant transformation of selfcells. Consequently, immunological self-tolerance can be maladapted to repress cancer-elicited immune responses. Indeed, multiple T cell self-tolerance regulators including Foxp3 + regulatory T (Treg) cells, co-inhibitory receptors PD-1 and CTLA-4, and the regulatory cytokine transforming growth factor-β (TGFβ) suppress immune control of tumor development [11][12][13][14][15] .Depletion of tumor-infiltrating Treg cells via genetic approaches or administration of anti-PD-1 and anti-CTLA-4 result in CTL-dependent cancer cell elimination in animal models and patients 16,17 . In transgenic mouse models of cancer, blockade of TGFβ signaling in T cells...

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Transforming Growth Factor-β Signaling in Immunity and Cancer

Cited by 1,459 publications

References 189 publications

Yap suppresses T cell function and infiltration in the tumor microenvironment

Yap suppresses T cell function and infiltration in the tumor microenvironment

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells

TGFβ Suppresses Type 2 Immunity to Cancer

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Transforming Growth Factor-β Signaling in Immunity and Cancer

Cited by 1,459 publications

References 189 publications

Yap suppresses T cell function and infiltration in the tumor microenvironment

Yap suppresses T cell function and infiltration in the tumor microenvironment

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

TGFβ Suppresses Type 2 Immunity to Cancer

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Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺T cells