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Cancer-driven myeloid cell dysfunction
Cancer-driven myeloid cell dysfunction. Immune homeostasis is maintained by an adequate balance of myeloid and lymphatic responses. In chronic inflammatory states, including cancer, this balance is disrupted due to the rapid expansion of myeloid cells and the inability to mature into functional inflammatory cells (neutrophils, macrophages, dendritic cells), resulting in Decline in anti-tumor lymphoid response.
Cancer-related inflammation is accompanied by the production of hematopoietic growth factors and cytokines, recruiting and activating myeloid precursor cells, leading to persistent chronic inflammation. Pathological chronic inflammation will change the metabolism of myeloid cells, coupled with tumor cells competing for essential nutrients, and hypoxia-induced metabolic reprogramming, can exacerbate this metabolic change.
Pathological myeloid cell production (Pathologic myelopoiesis)
Enhanced myeloid production is considered to be the main factor driving inflammatory diseases, including cancer. It is characterized by abnormal differentiation of myeloid progenitor cells, accumulation of dysfunctional myeloid cells with inhibitory function, including myeloid suppressor cells (MDSCs), resistant Tolerogenic dendritic cells (tDCs) and tumor-associated macrophages (TAMs).
Hematopoietic stem cells (HSCs) are continuously activated under the stimulus of chronic inflammation in cancer, or over-activated in the case of acute infection or sepsis, at the expense of lymphocyte production, leading to the expansion of immature and dysfunctional myeloid cells, which surrounds and depletes the resistance. Tumor immunity, leading to local and systemic host immune suppression. This pathological myeloid cell production leads to a pro-disease phenotype.
This is a paradox. Myeloid cell production is the body’s anti-tumor and anti-infective force, but abnormal pathological myeloid cell production promotes diseases and tumors.
Metabolism-tumor-related inflammation-myeloid cells-immunotherapy
Obesity and adipose tissue macrophages promote the expansion of myeloid cells by releasing various inflammatory cytokines and adipokines, activating transcription factors (PARs, RORC1/RORγ and C/EBPβ), and activating the proliferation and differentiation of HSCs.
Tumor cells can promote the expansion of myeloid cells, mainly by releasing a series of factors (CSFs, IL-1, IL-17, and PGE2) and up-regulating transcription factors (p50NF-κB, STAT3 and PU-1).
The production of adenosine, VEGF and IL-10 by cancer cells can induce the tumor-promoting phenotype of iDc (IL-10 high/IL-12 low). Then the newly emerged myeloid cells are recruited to the tumor site, the inhibitor phenotype (TAM, TAN, MDSC, and iDC) is obtained, and an immunosuppressive tumor microenvironment (TME) is established.
In the tumor microenvironment, cancer cells actively hinder the activation of T lymphocytes through depletion of amino acids, and infiltrating myeloid suppressor cells and cancer cells express immunosuppressive enzymes (IDO, INOS, and Arg1) to coordinate their participation in this activity. In particular, IDO activity leads to the production of the immunosuppressive catabolite kynurenine (Kyn), which can induce the expansion of regulatory T (Treg) cells.
Myeloid suppressor cells further express immune checkpoint ligands (such as PD-L1), which helps suppress anti-tumor immunity. The metabolism of obesity also promotes the transformation of macrophages from “M2-like” to “M1-like”, leading to inflammation-driven insulin resistance (IR).
It is worth noting that obesity and certain chemotherapy drugs (such as irinotecan, etoposide, and platinum) can induce IR, interfere with energy balance, and affect T cell activation. However, chemotherapy can also enhance anti-tumor immunity by promoting immunogenic cell death (ICD) of cancer cells (such as anthracyclines, DNA-damaging drugs) and eliminating MDSC (such as docetaxel, gemcitabine, and 5-fluorouracil).
At the same time, the inhibition of fatty acid oxidation significantly reduces the absorption of fatty acids and inhibits the immunosuppressive function of MDSC. In general, the crossover of the host’s metabolic status, tumor metabolism, cancer inflammation, and bone marrow production output quality strongly affects the response to treatment.
(source:internet, reference only)