IL-1-mediated cancer-adapted hematopoiesis in aging and clonal hematopoiesis.

Abstract

A defining and evolutionary-selected feature of hematopoiesis is its capacity to adapt to organismal cellular needs. This demand-adapted hematopoiesis relies on a complex peripheric immune system capable of sensing minute amounts of damage and pathogen molecular patterns and trigger an inflammation-based reaction that sets the organism on alert. At a receiver-end of this response are bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) which rapidly sense inflammatory messages and engage in differentiating divisions to replenish the consumed innate immune cells, bringing the organism back into homeostasis. Cancer can elicit such systemic inflammatory-immune response, possibly as an initial attempt to contain tumor progression, which pushes HSPC differentiation towards myeloid cells production (myelopoiesis) in a process here termed cancer-adapted hematopoiesis (CAH). CAH leads to proliferation and mobilization of HSPCs, causing extramedullary hematopoiesis (EMH) and increased myelopoietic output that, due to its accelerated nature, generates immature myeloid cells with immunosuppressive functions that support tumor progression, generally termed myeloid-derived suppressor cells (MDSC). While multiple inflammatory pathways are implicated in CAH, here we focus on the impact of IL-1 pathway, which is a well-established modulator of HSPC biology in contexts of sterile inflammation, infection and myeloablation. We present evidence for the IL-1 pathway as a central driver of CAH acting both as a direct and indirect agent between tumors and HSPCs. Moreover, we highlight recent models on how IL-1-mediated CAH is impacted by age and clonal disorders of the hematopoietic system, further highlighting its pathological and thus targetable role in cancer progression.