Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy

Zhang, Shuping; Wu, Meng; Wang, Fang

doi:10.1038/cmi.2018.170

Cited by 40 publications

(29 citation statements)

References 12 publications

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“…Traditionally defined CD4+FOXP3+ regulatory TILs have been identified in tumors previously and may play a role in tumor evasion and resistance of the patient's immune system 10 . However, only recently have a distinct population of CD8+ FOXP3+ regulatory T cells been identified in tumors and never before in cSCC 11 . These CD8+ FOXP3+ regulatory T cells may exhibit an even more potent regulatory function 12 .…”

Section: Patient Demographicsmentioning

confidence: 99%

Decreased cytotoxic T cells and TCR clonality in organ transplant recipients with squamous cell carcinoma

et al. 2020

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T-cell landscape differences between cutaneous squamous cell carcinoma (cSCC) tumors in immune competent (SCC in IC) and immunocompromised organ transplant recipients (TSCC in OTR) are unclear. We developed an analytical method to define tumor infiltrating lymphocyte (TIL) phenotype in cSCC from immune competent and immune suppressed patients using single-cell TCR sequencing and gene expression data. TSCC exhibits reduced proportions of cytotoxic and naïve TILs and similar numbers of regulatory TILs. Fewer, more heterogeneous TCR clonotypes are observed in TIL from OTR. Most TCR sequences for top ten clonotypes correspond to known antigens, while 24% correspond to putative neoantigens. OTR show increased cSCC events over 12 months possibly due to reduced cytotoxic T-cells. Our novel method of barcoding CD8+ T-cells is the first providing gene expression and TCR sequences in cSCC. Knowledge regarding putative antigens recognized by TCRs with phenotypic function of T-cells bearing those TCRs could facilitate personalized cSCC treatments.

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Section: Patient Demographicsmentioning

confidence: 99%

Decreased cytotoxic T cells and TCR clonality in organ transplant recipients with squamous cell carcinoma

et al. 2020

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“…TGF-β1 levels correlate positively with the percentage of CD8+ Treg cells in ovarian cancer, and high TGF-β1 expression triggers the suppressive function of in vitro-induced CD8+ Treg cells. It was recently reported that TGF-β1 secreted by ovarian cancer cells could generate CD8+ Treg cells in vitro from CD8+ T cells through engagement of the p38 MAPK signaling pathway [54]. TGF-β1 secreted by the tumor cells and CMV-infected macrophages might be an imperative factor for the differentiation of CD8+ Treg cells from effector CD8+T cells, thereby shifting the immune balance within the tumor from cytotoxic to an immunosuppressive state.…”

Section: Hcmv M2 and T Regulatory Cellsmentioning

confidence: 99%

A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity

Geisler

Touma

Rahbar

et al. 2019

Cancers

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Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.

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“…Those failures are linked to impaired iNKT cell function. Although previous studies suggest that TAMs [11][12][13] , myeloid derived suppressor cells 14 , regulatory T cells 15,16 , exosomes 17 , metabolic products 18,19 , and suppressive cytokines 20 in tumors repress anti-tumor immunity and cause the failure of immunotherapies, the mechanisms underlying dysfunction of intratumoral iNKT cells still remain unclear. Elucidating the underlying mechanisms would help to design new immunotherapies augmenting the efficacy of iNKT cell-based immunotherapies.…”

mentioning

confidence: 99%

Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells

Tian

et al. 2020

Nat Commun

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Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

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Immune regulation by CD8+ Treg cells: novel possibilities for anticancer immunotherapy

Cited by 40 publications

References 12 publications

Decreased cytotoxic T cells and TCR clonality in organ transplant recipients with squamous cell carcinoma

Decreased cytotoxic T cells and TCR clonality in organ transplant recipients with squamous cell carcinoma

A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity

Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells

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