Implications of metabolism-driven myeloid dysfunctions in cancer therapy

Abstract

Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.

Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

“…In cancer, the spleen is a key organ of extramedullary hematopoiesis and is responsible for the production of suppressive immune cells [ 98 ]. It is well established that cancer dysregulates hematopoiesis to generate MDSCs that suppress antitumor response [ 10 , 99 ]. However, during tumor progression, immune cells in the murine spleen are vastly outnumbered by another type of cells, EPCs [ 41 , 62 ].…”

Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights

“…Another emerging issue is the cross-talk between cancer metabolism and host related immune status, due to the relationship between metabolic impairment and chronic inflammation. In particular, current research is focused on the evaluation of aberrant myelopoiesis, leading to an immunosuppressive environment, possibly due to the accumulation of myeloid-derived suppressor cells (MDSCs) that suppress adaptive immunity favoring cancer cell proliferation [ 31 , 61 ].…”

Viewing Cancer Through the Lens of Corruption: Using Behavioral Ecology to Understand Cancer

“…Thus, the physical damage that should be an unambiguous signal of danger is not concealed but is instead turned to the tumor's own advantage. As part of this process, some cancer cells release cytokines that promote polarization of nearby immune cells to a pro-tumor role, dampening the anti-tumor immune response and stimulating cancer cell survival and proliferation (Cheng et al, 2019;Strauss et al, 2020). Immune cells can promote cancer progression through an "angiogenic switch" by producing proteases, proteins that break down the extracellular matrix, that in turn can activate latent molecules to drive angiogenesis (Ribatti et al, 2007;Baeriswyl and Christofori, 2009).…”