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Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNγ mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+-dependent immune homeostasis. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an "emergency state" that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease. [ABSTRACT FROM AUTHOR]

New evidences indicate that the metabolic instruction of immunity (immune metabolism) results from the integration of cell metabolism and whole-body metabolism, which are both influenced by nutrition, microbiome metabolites and disease-driven metabolism (e.g. cancer metabolism). Cancer metabolism influences the immunological homeostasis and promotes immune alterations that support disease progression, hence influencing the clinical outcome. Cancer cells display increased glucose uptake and fermentation of glucose to lactate, even in the presence of completely functioning mitochondria. A major side effect of this event is immunosuppression, characterized by limited immunogenicity of cancer cells and restriction of the therapeutic efficacy of anticancer immunotherapy. Here, we discuss how the metabolism of myeloid cells associated with cancer contributes to the differentiation of their suppressive phenotype and therefore to cancer immune evasion. [ABSTRACT FROM AUTHOR]

Cancer cells rewire their metabolism to promote growth, survival, proliferation and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate, which is observed even in the presence of completely functioning mitochondria. This effect is known as the ‘Warburg Effect’ and its intensive investigation in the last decade has partially established either its causes or its functions. It is now emerging that a major side effect of the Warburg Effect is immunosuppression, which limits the immunogenicity of cancer cells and therefore restricts the therapeutic efficacy of anticancer immunotherapy. Here we discuss how the metabolic communication between cancer and infiltrating myeloid cells contributes to cancer immune evasion and how the understanding of these mechanisms may improve current immunotherapies. [ABSTRACT FROM AUTHOR]

Abstract: Macrophages undergo a wide spectrum of polarized activation states, and have the potential both to elicit tumor and tissue destructive reactions and to promote tumor progression (macrophage balance). In general, tumor-associated macrophages (TAM) from established tumors and the related myeloid-derived suppressor cells are diverse and have properties of M2-activated cells. As such, they help cancer progression and metastasis. Therefore, TAM are a key component of pathways connecting inflammation and cancer. [Copyright &y& Elsevier]

Abstract: Macrophages are a fundamental part of the innate defense mechanisms, which can promote specific immunity by inducing T cell recruitment and activation. Despite this, their presence within the tumour microenvironment has been associated with enhanced tumour progression and shown to promote cancer cell growth and spread, angiogenesis and immunosuppression. This paradoxical role of macrophages in cancer finds an explanation in their functional plasticity, that may result in the polarized expression of either pro- or anti-tumoural functions. Key players in the setting of their phenotype are the microenvironmental signals to which macrophages are exposed, which selectively tune their functions within a functional spectrum encompassing the M1 and M2 extremes. Here, we discuss recent findings suggesting that targeting tumour-associated macrophages (TAMs) polarization may represent a novel therapeutic strategy against cancer. [Copyright &y& Elsevier]

Abstract: Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. In the tumor microenvironment neoplastic cells shape the differentiation and functional orientation of TAM which, in turn, express several protumoral functions, including secretion of growth factors and matrix-proteases, promotion of angiogenesis and suppression of adaptive immunity. This review analyzes our current knowledge of TAM and their involvement in tumor development and progression. The interplay between TAM and neoplastic cells represents a promising target of future therapeutic approaches. [Copyright &y& Elsevier]

An intrinsic (oncogene-driven) pathway and an extrinsic (microenvironment-driven) pathway connect inflammatory reactions and cancer. M2-polarized tumor-associated macrophages and the related myeloid-derived suppressor cells are key prototypic components of smoldering inflammation driving neoplastic progression. However, mononuclear phagocytes can exert anti-tumor activity by killing tumor cells and eliciting tissue disruptive reactions (M1), a likely scenario in the early phases of carcinogenesis of immunogenic tumors and following therapeutic intervention. Shifting the macrophage balance represents a viable therapeutic target. Herein, the ‘macrophage balance’ is discussed in the context of the apparent paradox of tumor promotion by innate immunity-driven inflammation and the seemingly opposed tumor surveillance by adaptive immune responses. [ABSTRACT FROM AUTHOR]

Abstract: Tumour-associated macrophages (TAM) represent the major inflammatory component of the stroma of many tumours, and can affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated pro-tumoural functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The pro-tumoural role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumours and poor patient prognosis. Evidence is presented here supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and are a potential target for anti-cancer therapy. [Copyright &y& Elsevier]

Abstract: It has been estimated that chronic infections with viruses, bacteria and parasites are the causative agents of 8–17% of global cancers burden. Carcinogenesis associated with infections is a complex process, often mediated by chronic inflammatory conditions and accumulating evidence indicate that a smouldering inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Selected infectious agents promote a cascade of events culminating in chronic inflammatory responses, thus predisposing target tissues to increased cancer susceptibility. A causal link also exists between an inflammatory microenvironment, consisting of inflammatory cells and mediators, and tumor progression. Tumor-Associated Macrophages (TAM) represent the major inflammatory population present in tumors, orchestrating various aspects of cancer, including: diversion and skewing of adaptive responses; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis; response to hormones and chemotherapeutic agents. Recent studies on human and murine tumors indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, during tumour development. In established tumors, TAM acquire an M2 polarized phenotype are engaged in immunosuppression and the promotion of tumor angiogenesis and metastasis. Being a first line of the innate defence mechanisms, macrophages are also equipped with pathogen-recognition receptors, to sense the presence of danger signals, including onco-pathogens. Here we discuss the evidence suggesting a causal relationship between selected infectious agents and the pro-tumoral reprogramming of inflammatory cells, as well as its significance in tumor development. Finally, we discuss the implications of this phenomenon for both cancer prevention and therapy. [Copyright &y& Elsevier]

Abstract: Several experimental and epidemiological evidence indicate that, irrespective of the trigger for the development (chronic infection/inflammation or genetic alteration), a “smouldering” inflammation is associated with the most of, if not all, tumours and supports their progression. Several evidence have highlighted that tumours promote a constant influx of myelomonocytic cells that express inflammatory mediators supporting pro-tumoral functions. Myelomonocytic cells are key orchestrators of cancer-related inflammation associated with proliferation and survival of malignant cells, subversion of adaptive immune response, angiogenesis, stroma remodelling and metastasis formation. Although the connection between inflammation and cancer is unequivocal the mechanistic basis of such association are largely unknown. Recent advances in the understanding of the cellular and molecular pathways involved in cancer-related inflammation as well as their potential relevance as diagnostic, prognostic and therapeutic targets are herein discussed. [Copyright &y& Elsevier]

Chronic and persistent inflammation contributes to cancer development and can predispose to carcinogenesis. Infection-driven inflammations are involved in the pathogenesis of approximately 15–20% of human tumors. However, even tumors that are not epidemiologically linked to pathogens are characterized by the presence of an inflammatory component in their microenvironment. Hallmarks of cancer-associated inflammation include the presence of infiltrating leukocytes, cytokines, chemokines, growth factors, lipid messengers, and matrix-degrading enzymes. Schematically, two interrelated pathways link inflammation and cancer: (1) genetic events leading to neoplastic transformation promote the construction of an inflammatory milieu; (2) tumor-infiltrating leukocytes, in particular macrophages, are prime regulators of cancer inflammation. Thus, an intrinsic pathway of inflammation (driven in tumor cells), as well as an extrinsic pathway (in tumor-infiltrating leukocytes) have been described and both contribute to tumor progression. [Copyright &y& Elsevier]