Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

Abstract

Over the last decades, cancer immunotherapies such as checkpoint blockade and adoptive T cell transfer have been a game changer in many aspects and have improved the treatment for various malignancies considerably. Despite the clinical success of harnessing the adaptive immunity to combat the tumor, the benefits of immunotherapy are still limited to a subset of patients and cancer types. In recent years, neutrophils, the most abundant circulating leukocytes, have emerged as promising targets for anti-cancer therapies. Traditionally regarded as the first line of defense against infections, neutrophils are increasingly recognized as critical players during cancer progression. Evidence shows the functional plasticity of neutrophils in the tumor microenvironment, allowing neutrophils to exert either pro-tumor or anti-tumor effects. This review describes the tumor-promoting roles of neutrophils, focusing on their myeloid-derived suppressor cell activity, as well as their role in tumor elimination, exerted mainly via antibody-dependent cellular cytotoxicity. We will discuss potential approaches to therapeutically target neutrophils in cancer. These include strategies in humans to either silence the pro-tumor activity of neutrophils, or to activate or enhance their anti-tumor functions. Redirecting neutrophils seems a promising approach to harness innate immunity to improve treatment for cancer patients.

Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

“…7f ). These results are consistent with a pro-tumor role of IL-17 and possibly neutrophils in aggressive niches, as has been described for N2 neutrophils and/or granulocytic myeloid-derived suppressor cells (G-MDSCs) 50 , 51 .…”

“…In particular, we identified that S100A8+ neutrophils specifically infiltrated aggressive niches, which also displayed increased IL-17 signaling. Tumor-associated neutrophils, or TANs, have been reported to play dual roles in the tumor microenvironment, including in breast cancer 51 , 89 – 91 . The functional role of TANs in DCIS, which have been shown to increase compared to normal tissue, is not known, but may be similarly double-sided 19 , 92 .…”

Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

“…Finally, when compared with a population of animals identically treated with isotype control (pooled from multiple cohorts), animals treated with anti-IL-17 showed delayed latency to a palpable tumor (Fig 7F). These results are consistent with a pro-tumor role of IL-17 and possibly neutrophils in aggressive niches, as has been described for N2 neutrophils and/or granulocytic myeloid derived suppressor cells (G-MDSCs) (Furumaya et al, 2020;Ostrand-Rosenberg and Fenselau, 2018).…”

“…In particular, we identi ed that S100A8+ neutrophils speci cally in ltrated aggressive niches, which also displayed increased IL-17 signaling. Tumor-associated neutrophils, or TANs, have been reported to play dual roles in the tumor microenvironment, including in breast cancer (Fridlender et al, 2009;Furumaya et al, 2020;Jaillon et al, 2020;Mishalian et al, 2013). The functional role of TANs in DCIS, which have been shown to increase compared to normal tissue, is not known, but may be similarly double-sided (Gil Del Alcazar et al, 2017;Nelson et al, 2018).…”

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy

“…A substantial amount of preclinical and clinical studies has indicated that tumor-associated myeloid cells, predominantly tumorassociated macrophages (TAMs), neutrophils, and myeloidderived suppressor cells (MDSCs), sustain an immunosuppressive tumor microenvironment, which is particularly refractory to both T cell trafficking and antitumor T cell functions (4,(129)(130)(131)(132)(133)(134). Extensive research in this field has additionally concluded that the specific targeting and/or elimination of this myeloid-driven immunosuppressive program can render the natural, induced, and engineered immunological responses against tumors more concrete and effective (135)(136)(137). In line with the above, here we first provide proof-of-principle evidence of this notion using the Mouse Mammary Tumor Virus Polyoma Middle-T antigen (MMTV-PyMT) mouse model of breast carcinoma, which successfully recapitulates human breast cancer progression (138).…”