Tumor-Associated Neutrophils Dampen Adaptive Immunity and Promote Cutaneous Squamous Cell Carcinoma Development

Khou, Sokchea; Popa, Alexandra; Luci, Carmelo; Bihl, Franck; Meghraoui-Kheddar, Aïda; Bourdely, Pierre; Salavagione, Emie; Cosson, Estelle; Rubod, Alain; Cazareth, Julie; Barbry, Pascal; Mari, Bernard; Rezzonico, Roger; Anjuère, Fabienne; Braud, Véronique M.

doi:10.3390/cancers12071860

Cited by 31 publications

(33 citation statements)

References 57 publications

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“…During inflammation, neutrophils are among the first phagocytes to infiltrate the tissue, mostly through CXC chemokine-mediated chemotaxis, and these cells predominate in the SCC invasive front ( Kruger et al, 2015 ; Simonneau et al, 2018 ; Khou et al, 2020 ). Progressive infiltration of tumor-associated neutrophils (TANs) was observed during the evolution of benign papillomas to established SCC lesions in a chemical carcinogenesis model, and tumor escape mostly involved the impairment of anti-tumor CD8 + T cell responses mediated by high arginase activity, production of reactive oxygen species (ROS), nitrite (NO), and the induction of PD-1 expression on CD8 + T cells ( Khou et al, 2020 ; Figure 1C ). Similar to CAFs, TANs can also play an anti-tumoral effect in SCC.…”

Section: Cellular Composition Of the Tumor Microenvironmentmentioning

confidence: 99%

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Amôr

Santos

Campanelli

2021

Front. Cell Dev. Biol.

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Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

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Section: Cellular Composition Of the Tumor Microenvironmentmentioning

confidence: 99%

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Amôr

Santos

Campanelli

2021

Front. Cell Dev. Biol.

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“…Inflammation is closely related to the development of various cancers including Open access melanoma, with its pivotal role in the regulation of cancer immune response demonstrated recently. [13][14][15] To be specific, tumor necrosis factor-α (TNF-α) that is a common proinflammatory cytokine and its downstream pathway could induce tumor immune escape by elevating the expressions of immune checkpoint molecules. 13 16 On the other, TNF-α is also one of the major cytokines secreted by activated CD8 + T cells in tumor microenvironment that potentiates antitumor immune response.…”

Section: Introductionmentioning

confidence: 99%

A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma

Guo

et al. 2020

J Immunother Cancer

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BackgroundThe therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.MethodsThe association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.ResultsWe first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden.ConclusionsTogether, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.

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“…In advanced stages of primary melanomas, TAN were shown as expressing PD-L1, CXCR4, CCR5, Adam17, and Nos2, leading to the immunosuppression of T-cell proliferation [ 154 ]. The expression of PD-L1 by TAN was correlated with the induction of PD-1 on CD8 T cells and their in vivo depletion delayed tumor growth with a significant increase of the frequency of proliferating IFN-γ-producing CD8 T cells [ 155 ]. Besides, the expression of PD-L1 by neutrophils can be promoted by IL-6 that is produced by human ovarian tumor cells under the effect of long non-coding RNA [ 156 ].…”

Section: Neutrophilsmentioning

confidence: 99%

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

Domagala

Laplagne

Leveque

et al. 2021

Cancers

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Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their individual roles in interaction between malignant cells, and the formation of the tumor microenvironment (TME). In this review, we focus on the myeloid cell compartment, a prominent, and heterogeneous group populating TME, which can initially exert an anti-tumoral effect, but with time actively participate in disease progression. Macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells, eosinophils, and basophils act alone or in concert to shape tumor cells resistance through cellular interaction and/or release of soluble factors favoring survival, proliferation, and migration of tumor cells, but also immune-escape and therapy resistance.

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Tumor-Associated Neutrophils Dampen Adaptive Immunity and Promote Cutaneous Squamous Cell Carcinoma Development

Cited by 31 publications

References 57 publications

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

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