Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFα and NO-dependent mechanism, promoting a tumor-supportive environment

Abstract

The role of neutrophils in tumor progression has become in recent years a subject of growing interest. Tumor-associated neutrophils (TANs), which constitute an important portion of the tumor microenvironment, promote immunosuppression in advanced tumors by modulating the proliferation, activation and recruitment of a variety of immune cell types. Studies which investigated the consequences of manipulating TAN polarization suggest that the impact of these neutrophils on tumor progression is considerably mediated by and dependent on the presence of CD8 T-cells. It has been previously shown that granulocytic myeloid regulatory cells, i.e. TANs and granulocytic myeloid-derived suppressor cells (G-MDSCs) are capable of suppressing CD8 T-cell proliferation and affect their activation. In the current study, we find that in addition, TANs isolated from different models of murine cancer promote immunosuppression by strongly inducing CD8 T-cell apoptosis. We demonstrate that the TNFα pathway in TANs is critical for the induction of apoptosis, and that the mechanism through which apoptosis is induced involves the production of NO, but not ROS. In the absence of pre-activation, TANs are capable of activating CD8 T-cells, but specifically induce the apoptosis of non-activated CD8CD69 cells. Despite this contradictive effect on T-cell function, we show that TANs suppress the anti-tumor effect of CD8 T-cells and abolish their ability to delay tumor growth. Our results add another important layer on the understanding of the possible mechanisms by which TANs regulate the anti-tumor immune response mediated by CD8 T-cells, therefore promoting a tumor-supportive environment.

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

“…In contrast, N2 TANs isolated from advanced tumors promote CD8 + T cell death . Although N2 TANs were reported in this study to activate CD8 + T cells, they simultaneously induce apoptosis preferentially in the nonactivated CD8 + T cells . These results nicely example the fact that TANs can display concurrently both tumor‐supportive and suppressive properties.…”

“…The presence of CD8 + T cells appears to be critical for the antitumor effect of N1 TAN function, since CD8 + cells depletion in mice impairs neutrophil mobilization and blocks the anti-TGFb effect on tumor size [90]. In contrast, N2 TANs isolated from advanced tumors promote CD8 + T cell death [84]. Although N2 TANs were reported in this study to activate CD8 + T cells, they simultaneously induce apoptosis preferentially in the nonactivated CD8 + T cells [84].…”

Recent advances on the crosstalk between neutrophils and B or T lymphocytes

“…As far as murine TANs, there is a general consensus in the field that, similar to the macrophage M1/M2 polarization, TANs can also switch from an antitumorigenic N1 phenotype, evident during the early phases of tumour growth, to a pro‐tumorigenic N2 phenotype acquired during tumour progression . The ability of N2 TANs to inhibit the CD8 + T‐cell antitumoral immune response is one of the main mechanisms through which these cells have been shown to favour tumour progression . In this context, TANs isolated from different models of murine cancer have been shown to promote immunosuppression by strongly inducing CD8 + T‐cell apoptosis via tumour necrosis factor‐ α and nitric oxide‐dependent mechanisms …”

“…The ability of N2 TANs to inhibit the CD8 + T‐cell antitumoral immune response is one of the main mechanisms through which these cells have been shown to favour tumour progression . In this context, TANs isolated from different models of murine cancer have been shown to promote immunosuppression by strongly inducing CD8 + T‐cell apoptosis via tumour necrosis factor‐ α and nitric oxide‐dependent mechanisms …”

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

“…78,79 These cells are able to directly suppress T cell responses and inhibit CD8 T cell infiltration resulting in impaired anti-tumour activity. [78][79][80][81][82] Collectively, this autocrine cascade promotes tumour growth and metastasis. In our model, the blockage of CXCR2 enriched the anti-tumour immune cell compartment and significantly reduced metastatic spread, which highly supports our concept.…”