Abstract
Cancer progression generates a chronic inflammatory state that dramatically influences hematopoiesis, originating different subsets of immune cells that can exert pro- or anti-tumor roles. Commitment towards one of these opposing phenotypes is driven by inflammatory and metabolic stimuli derived from the tumor-microenvironment (TME). Current immunotherapy protocols are based on the reprogramming of both specific and innate immune responses, in order to boost the intrinsic anti-tumoral activity of both compartments. Growing pre-clinical and clinical evidence highlights the key role of metabolism as a major influence on both immune and clinical responses of cancer patients. Indeed, nutrient competition (i.e., amino acids, glucose, fatty acids) between proliferating cancer cells and immune cells, together with inflammatory mediators, drastically affect the functionality of innate and adaptive immune cells, as well as their functional cross-talk. This review discusses new advances on the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of metabolic interventions as modulators of anticancer immune responses and catalysts of anticancer immunotherapy.
Highlights
Hematopoiesis consists of a rigorous series of cell lineage commitments that regulate the differentiation of hematopoietic stem cells (HSCs) into lymphoid and myeloid progenitors and subsequently to mature immune cells necessary to maintain the physiological levels of circulating leukocytes [1]
The approved Sipuleucel-T for the treatment of metastatic prostate cancer is generated by challenging ex vivo Dendritic cell (DC) with recombinant prostatic acid phosphatase (PAP) antigen fused with GM-CSF, which enhances antigen presentation and activation of T cells against tumor cells [93]
A large part of patients undergoing immunotherapy display unresponsiveness or severe side effects, highlighting the need for new studies that might improve our understanding of the mechanisms guiding these therapeutic limitations
Summary
Hematopoiesis consists of a rigorous series of cell lineage commitments that regulate the differentiation of hematopoietic stem cells (HSCs) into lymphoid and myeloid progenitors and subsequently to mature immune cells necessary to maintain the physiological levels of circulating leukocytes [1]. Despite some degree of functional overlap, chemokines and complement components (i.e., CCL2, C5a) are specialized determinants of macrophage recruitment in tumors, while inflammatory cytokines (i.e., IL-1β and IL-6) and myeloid growth factors (i.e., M-CSF, GM-CSF, G-CSF) critically orchestrate emergency myelopoiesis [6,7] The latter act through activation of specific transcription factors that differentially drive terminal maturation of immune cells [7]. The systemic deregulation of lipid metabolism in obese subjects appears increasingly relevant in modulating cancer-related inflammation [26], expansion of myeloid cells and inflammatory phenotypes [27,28] Within this scenario, therapeutic interventions modulating key molecular players of lipid metabolism appear promising tools for the antitumor reprogramming of TAMs and MDSCs, able to restore effective anti-tumor immunity. We discuss the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of interventions in lipid metabolism as modulators of anticancer immune responses and catalysts of anticancer immunotherapy
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