Abstract
Production of nitric oxide (NO) has been demonstrated in several malignancies, however its role remains not fully understood, specifically in relation to the metabolic and functional implications that it may have on immune cells participating in tumorigenesis. Here, we show that inducible NO synthase (iNOS) is expressed in cancers of the colon and the prostate, mainly by tumour cells, and NO generation is evidenced by widespread nitrotyrosine (NT) staining in tumour tissue. Furthermore, presence of NT is observed in the majority of tumour-associated macrophages (TAMs), despite low iNOS expression by these cells, suggesting that NO from the tumour microenvironment affects TAMs. Indeed, using a co-culture model, we demonstrate that NO produced by colon and prostate cancer cells is sufficient to induce NT formation in neighbouring macrophages. Moreover, exposure to exogenous NO promotes mitochondria-dependent and -independent changes in macrophages, which orientate their polarity towards an enhanced pro-inflammatory phenotype, whilst decreasing antigen-presenting function and wound healing capacity. Abrogating endogenous NO generation in murine macrophages, on the other hand, decreases their pro-inflammatory phenotype. These results suggest that the presence of NO in cancer may regulate TAM metabolism and function, favouring the persistence of inflammation, impairing healing and subverting adaptive immunity responses.
NO favours tumour-promoting inflammation by its actions on macrophages. (1) NO within the tumour microenvironment acts on macrophages, leading to phenotypic alterations (2–4) that may favour the persistence of inflammation, impair healing and subvert adaptive immunity responses, thus contributing to tumour-promoting inflammation (created with BioRender.com). [Display omitted]
•Nitric oxide (NO) from the cancer microenvironment acts on tumour-associated macrophages (TAMs).•NO induces a phenotypic shift in macrophages through mitochondria-dependent and -independent pathways.•NO favours pro-inflammatory cytokine production whilst decreasing macrophage function as antigen presenting cell.•NO impairs repair function of macrophages.•Presence of NO in cancer may regulate TAM metabolism and function, favouring tumour-promoting inflammation.