Tumor-associated Tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells

Noyes, David; Bag, Arup K.; Oseni, Saheed Oluwasina; Semidey-Hurtado, Jon; Cen, Ling; Sarnaik, Amod A.; Sondak, Vernon K.; Adeegbe, Dennis O.

doi:10.1136/jitc-2022-004605

Cited by 40 publications

(22 citation statements)

References 51 publications

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“…The above observations support the notion that IL-37 may exert tumor-protective immune functions. However, it should also be noted that our analyses revealed some, at first sight, conflicting evidence: IL-37 expression levels correlated positively with the rate of infiltration by regulatory T cells, as well as M2 MΦ, that have been reported to exert pro-tumoral and anti-tumor immunity actions in LUAD [ 97 , 98 ]. The molecular and cellular networks responsible for these phenotypes need further investigation.…”

Section: Discussionmentioning

confidence: 80%

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma

et al. 2022

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Interleukin-37 (IL-37) is a relatively new IL-1 family cytokine that, due to its immunoregulatory properties, has lately gained increasing attention in basic and translational biomedical research. Emerging evidence supports the implication of this protein in any human disorder in which immune homeostasis is compromised, including cancer. The aim of this study was to explore the prognostic and/or diagnostic potential of IL-37 and its receptor SIGIRR (single immunoglobulin IL-1-related receptor) in human tumors. We utilized a series of bioinformatics tools and -omics datasets to unravel possible associations of IL-37 and SIGIRR expression levels and genetic aberrations with tumor development, histopathological parameters, distribution of tumor-infiltrating immune cells, and survival rates of patients. Our data revealed that amongst the 17 human malignancies investigated, IL-37 exhibits higher expression levels in tumors of lung adenocarcinoma (LUAD). Moreover, the expression profiles of IL-37 and SIGIRR are associated with LUAD development and tumor stage, whereas their high mRNA levels are favorable prognostic factors for the overall survival of patients. What is more, IL-37 correlates positively with a LUAD-associated transcriptomic signature, and its nucleotide changes and expression levels are linked with distinct infiltration patterns of certain cell subsets known to control LUAD anti-tumor immune responses. Our data indicate the potential value of IL-37 and its receptor SIGIRR to serve as biomarkers and/or immune-checkpoint therapeutic targets for LUAD patients. Further, the data highlight the urgent need for further exploration of this cytokine and the underlying pathogenetic mechanisms to fully elucidate its implication in LUAD development and progression.

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Section: Discussionmentioning

confidence: 80%

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma

et al. 2022

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“…In cancer, Tregs mediate the dysfunction of the CD8 + T cells, which is characterized by upregulation of surface inhibitory receptors (e.g., CTLA-4). Furthermore, Treg-mediated IL-2 deprivation can exacerbate this dysregulation, leading to immune escape ( 96 ). Whether Tregs can cause ICI resistance is inconclusive, but some studies suggest its possible role in ICIs resistance.…”

Section: Drug Resistance Mechanismmentioning

confidence: 99%

Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Zhou

Zhao

et al. 2023

Front. Immunol.

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Immune checkpoint inhibitors (ICIs) in the form of anti-CTLA-4 and anti-PD-1/PD-L1 have become the frontier of cancer treatment and successfully prolonged the survival of patients with advanced non-small cell lung cancer (NSCLC). But the efficacy varies among different patient population, and many patients succumb to disease progression after an initial response to ICIs. Current research highlights the heterogeneity of resistance mechanisms and the critical role of tumor microenvironment (TME) in ICIs resistance. In this review, we discussed the mechanisms of ICIs resistance in NSCLC, and proposed strategies to overcome resistance.

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“…Accumulation of Tregs in the TME has been correlated with poor prognosis in many solid tumors [ 58 ]. A recent study reveals that obstruction of antitumor immunity by Tregs is due to promotion of T cell dysfunction and to restricting clonal diversity in CD8+ TILs [ 58 ].…”

Section: The Tumor Microenvironmentmentioning

confidence: 99%

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

Schirrmacher¹,

Gool²,

Stuecker³

2022

IJMS

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An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as “concomitant immunity” suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

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Tumor-associated Tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells

Cited by 40 publications

References 51 publications

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma

Aberrant Expression and Prognostic Potential of IL-37 in Human Lung Adenocarcinoma

Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

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