Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells

Tekgüç, Murat; Wing, James B.; Osaki, Motonao; Long, Jia; Sakaguchi, Shimon

doi:10.1073/pnas.2023739118

Cited by 169 publications

(98 citation statements)

References 53 publications

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“…Depletion of CCR8 + Tregs induced potent and less exhausted CD4 + and CD8 + effector T cells, with up-regulated CD80/CD86 expression on antigen-presenting cells (APCs), leading to the development of tumor antigen-specific effector/memory CD8 + T cells. Tregs are efficient in suppressing antigen-dependent activation of naïve T cells via downregulating CD80/CD86 expression by APCs and in inhibiting PD-1 + effector T cells via up-regulating PD-L1 on APCs ( 47 , 48 ). Once potent tumor-specific effector Tconvs are induced, they are more resistant than naïve Tconvs to Treg suppression.…”

Section: Discussionmentioning

confidence: 99%

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Kidani

Nogami

Yasumizu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8+ Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8–. CCR8+ tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8+ effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.

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Section: Discussionmentioning

confidence: 99%

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Kidani

Nogami

Yasumizu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Forkhead box protein P3 (FOXP3) expressing regulatory T (T reg ) cells are a subset of CD4 + T cells with high immunosuppressive activity, which is critical cells for maintaining dominant self-tolerance and immune homeostasis ( Togashi et al, 2019 ). T reg cells exert their immunosuppressive activity through various cellular and humoral mechanisms, including cytotoxic T lymphocyte antigen 4 (CTLA-4)-mediated suppression of APCs, consumption of IL-2, and production of immune inhibitory cytokines and molecules ( Spolski et al, 2018 ; Tekguc et al, 2021 ). T reg cells can suppress anti-tumor immunity, and T reg cells dysregulation is associated with a poor prognosis in human cancer patients ( Wang and Ke, 2011 ; Saito et al, 2016 ).…”

Section: Vaccines Targeting P53mentioning

confidence: 99%

Clinical and Immunological Effects of p53-Targeting Vaccines

Zhou

Zeng

Young

et al. 2021

Front. Cell Dev. Biol.

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Immunotherapy, including immune checkpoint blockade and chimeric antigen receptor T cells, is one of the most promising approaches to treat cancer. Vaccines have been effective in preventing cancers like liver cancer and cervical cancer with a viral etiology. Instead of preventing disease, therapeutic cancer vaccines mobilize the immune system to attack existing cancer. p53 is dysregulated in the majority of human cancers and is a highly promising target for cancer vaccines. Over twenty clinical trials have targeted p53 in malignant diseases using vaccines. In this work, we review the progress of vaccinations with p53 or its peptides as the antigens and summarize the clinical and immunological effects of p53-targeting vaccines from clinical trials. The delivery platforms include p53 peptides, viral vectors, and dendritic cells pulsed with short peptides or transduced by p53-encoding viruses. These studies shed light on the feasibility, safety, and clinical benefit of p53 vaccination in select groups of patients, implicating that p53-targeting vaccines warrant further investigations in experimental animals and human studies.

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“…CTLA-4 or even its truncated form without the cytoplasmic portion regulates the expression of CD80/86 on the surface of APCs during Treg-APC conjugation and immune synapse formation. This process allows CLTA-4 to remove CD80/86 on APC surface via a trogocytosis mechanism, followed by trans-endocytosis for intracellular degradation ( 40 , 42 , 43 ). Decreased CD80/86 expression on APC surface reduces CD28-mediated T-cell stimulation due to cell-extrinsic ligand depletion ( 40 ), causes CD80/programed death ligand-1 (PD-L1) heterodimer disruption, and increases free PD-L1 levels from the APCs ( 43 ) ( Figure 1 ).…”

Section: Regulatory T-cell Immunosuppressive Function Regulationmentioning

confidence: 99%

“…This process allows CLTA-4 to remove CD80/86 on APC surface via a trogocytosis mechanism, followed by trans-endocytosis for intracellular degradation ( 40 , 42 , 43 ). Decreased CD80/86 expression on APC surface reduces CD28-mediated T-cell stimulation due to cell-extrinsic ligand depletion ( 40 ), causes CD80/programed death ligand-1 (PD-L1) heterodimer disruption, and increases free PD-L1 levels from the APCs ( 43 ) ( Figure 1 ). Tregs in VAT express CD36 to uptake long-chain fatty acid and contribute to lipid accumulation in obese subjects ( 44 ).…”

Section: Regulatory T-cell Immunosuppressive Function Regulationmentioning

confidence: 99%

Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy

2022

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Regulatory T cells (Tregs) are a subset of CD4+ T cells with their immunosuppressive activities to block abnormal or excessive immune responses to self and non-autoantigens. Tregs express the transcription factor Foxp3, maintain the immune homeostasis, and prevent the initiation of anti-tumor immune effects in various ways as their mechanisms to modulate tumor development. Recognition of different phenotypes and functions of intratumoral Tregs has offered the possibilities to develop therapeutic strategies by selectively targeting Tregs in cancers with the aim of alleviating their immunosuppressive activities from anti-tumor immune responses. Several Treg-based immunotherapeutic approaches have emerged to target cytotoxic T lymphocyte antigen-4, glucocorticoid-induced tumor necrosis factor receptor, CD25, indoleamine-2, 3-dioxygenase-1, and cytokines. These immunotherapies have yielded encouraging outcomes from preclinical studies and early-phase clinical trials. Further, dual therapy or combined therapy has been approved to be better choices than single immunotherapy, radiotherapy, or chemotherapy. In this short review article, we discuss our current understanding of the immunologic characteristics of Tregs, including Treg differentiation, development, therapeutic efficacy, and future potential of Treg-related therapies among the general cancer therapy.

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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells

Cited by 169 publications

References 53 publications

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Clinical and Immunological Effects of p53-Targeting Vaccines

Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy

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