The diagram illustrates the development of myeloid cells in cancer, highlighting different trajectories and factors involved. The process is divided into three distinct trajectories: Section (A) shows how tumor-derived factors like I L-4, G M-C S F, G-C S F, and I L-1 beta drive the expansion of M P P 3, G M P, and c M o P cells into immature and mature neutrophils and monocytes. Section (B) highlights how therapeutic interventions such as beta-glucan B C G treatment or the blockade of I L-1 beta and I L-4 R reprogram H S P C s to generate trained myeloid cells with anti-tumoral properties, increased phagocytic capacity, and enhanced C D 8 plus T cell infiltration. Section (C) depicts how C H I P-mutated H S P C s (including T E T 2, D N M T 3 A, and P P M 1 D mutations) outcompete wild-type cells, leading to altered differentiation trajectories that result in pro-fibrotic monocytes, impaired neutrophil function, and a state of chronic inflammation characterized by elevated I L-1 beta, I L-6, and T N F.
Emerging developmental trajectories for myeloid cells in cancer. (A) The first trajectory describes an increase in myeloid cell production (immNeus and monocytes) arising from GMPs, CMPs, and cMoPs. (B) In the myeloid trajectories shown in B, HSPC reprogramming occurs upon TI (BCG and β-glucan) and upon blockade of IL4R, IL1R, and with anakinra, giving rise to reprogrammed anti-tumoral myeloid cells. (C) In C, CHIP-mutated HSPCs can outcompete WT HSPCs (as in TET2 LOF) and rapidly generate myeloid cells. Other CHIP mutations (DNMT3A and PPM1D) coexist with WT cells and require either time (aging) or cytotoxic damage (chemotherapy) to facilitate expansion. HSPC differentiation trajectories driven by CHIP mutations, as well as the functions of myeloid cells harboring CHIP mutations, are only beginning to be appreciated. GMPs, granulocyte-MPs; NRF2, nuclear factor erythroid 2–related factor 2; Ag, antigen; LOF, loss-of-function.