IL8, Neutrophils, and NETs in a Collusion against Cancer Immunity and Immunotherapy

Abstract

One of the most important mechanisms by which cancer fosters its own development is the generation of an immune microenvironment that inhibits or impairs antitumor immune responses. A cancer permissive immune microenvironment is present in a large proportion of the patients with cancer who do not respond to immunotherapy approaches intended to trigger preexisting antitumor immune responses, for instance, immune checkpoint blockade. High circulating levels of IL8 in patients with cancer quite accurately predict those who will not benefit from checkpoint-based immunotherapy. IL8 has been reported to favor cancer progression and metastases via different mechanisms, including proangiogenesis and the maintenance of cancer stem cells, but its ability to attract and functionally modulate neutrophils and macrophages is arguably one of the most important factors. IL8 does not only recruit neutrophils to tumor lesions, but also triggers the extrusion of neutrophil extracellular traps (NET). The relevance and mechanisms underlying the contribution of both neutrophils and NETs to cancer development and progression are starting to be uncovered and include both direct effects on cancer cells and changes in the tumor microenvironment, such as facilitating metastasis, awakening micrometastases from dormancy, and facilitating escape from cytotoxic immune cells. Blockade of IL8 or its receptors (CXCR1 and CXCR2) is being pursued in drug development, and clinical trials alone or in combination with anti-PD-L1 checkpoint inhibitors are already ongoing.

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL‐8

“…Such a function cannot be addressed in mice since IL-8 is absent from the genome of rodents, precluding direct preclinical experiments. In our hands IL-8 immunostaining shows positive association with NETs suggesting that this factor is involved, although other mediators enriched in the tumour microenvironment probably also contribute [15]. Such a correlation is also found between serum IL-8 concentrations and NET presence in the circulation.…”

“…This study offers unambiguous evidence for NETosis in human cancer. According to mouse models, NETs are elements that exacerbate cancer progression through multiple mechanisms [15,41]. Neutrophils in these experimental settings and in cancer patients are perceived as procancer elements, even though there is some controversy regarding other putative anti-cancer mechanisms mediated by neutrophils [42][43][44].…”

“…Importantly, these include CXCL ELR + chemokines that are abundantly produced in tumour tissue microenvironments [13,14]. In human cancer, CXCL8 (Interleukin-8, IL-8) seems to be the most copiously CXCL ELR + present chemokine [15]. IL-8 not only induces NETosis when present in relatively high concentrations but also seems to be the most prominent chemoattractant for neutrophils in humans [16,17].…”

“…IL-8 not only induces NETosis when present in relatively high concentrations but also seems to be the most prominent chemoattractant for neutrophils in humans [16,17]. Neutrophils and myeloidderived suppressor cells exert pro-tumour activities, largely by inducing interference with antitumour immunity, although neutrophils may also mediate some anticancer actions [15,18].…”

Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade

“…In comparison to other biomarkers, the analysis of circulating markers may be easy, relatively cheap and non-invasive. Immune cell counts, lymphocytes phenotype and serum protein signature such as IL-8 have been suggested to be associated with clinical outcome of cancer patients who were primarily treated with ICB (96)(97)(98)(99)(100). In addition, the serum tumor markers and circulating tumor DNA were also observed to be associated with response (101)(102)(103).…”