Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation

Abstract

Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8+ T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment.

The research progress in the interaction between Candida albicans and cancers

“…Tregs have been shown to enhance tumor progression by inhibiting antitumor immune response (Deng et al, 2013;Lainé et al, 2021). However, the specific mechanism by which C. albicans promotes occurrence and development of breast cancer remains unknown.…”

“…It further shows that systemic infection of C. albicans could not only induce Tregs, but also lead to the imbalance of cytokine network, so as to promote the growth of tumor ( Ahmadi et al, 2019 ; Table 1 ). Tregs have been shown to enhance tumor progression by inhibiting antitumor immune response ( Deng et al, 2013 ; Lainé et al, 2021 ). However, the specific mechanism by which C. albicans promotes occurrence and development of breast cancer remains unknown.…”

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“…The tumor microenvironment (TME) is increasingly recognized as having a key role in tumor progression, largely due to the interactions between cancer, immune, vascular and stromal cells that take place in and around the tumor site. One distinct characteristic of the TME is its high levels of TGF-β (transforming growth factor beta), which is regarded as a key cytokine in promotion of immunosuppression ( 3 ). Tregs, which are typically characterized by an up-regulated expression of forkhead box P3 (FoxP3) , are found in high proportions within the TME of most cancers.…”

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“…It has been proven that the tumor microenvironment is not well established in MSS patients and subsequently limits an efficient anti-tumor immune response. 25 In addition to immune checkpoints, the tumor microenvironment contains other relevant molecules that play a role in immunosuppression including the cytokine TGF β. 26 TGF β has been shown to prevent the activation of T-cells, as well as decrease the function of both T and NK cells.…”