Dissecting the hematopoietic pathways governing age-associated pathogenic myelopoiesis

Chronic inflammation is a key factor contributing to age-related risks of tumor occurrence and progression. Myeloid cells of the immune system, such as monocytes and macrophages, play crucial roles in maintaining homeostasis and regulating inflammation. Besides their role in initiating the immune response, tissue-resident macrophages (TRMs) are essential for resolving inflammation and repairing tissues. TRMs are established during embryonic development and can persist into adulthood. However, a gradual replacement of embryonic- derived TRMs by monocyte-derived macrophages is suspected to contribute to tissue inflammation. Our previous research has demonstrated that myelopoiesis in response to tumorigenesis is pathogenic, with tumor-infiltrating mo-macs impairing immune control of lung tumors. In aged mice, we found that the aging of the immune system, independent of stromal age, drives tumor progression, and that hematopoietic aging promotes tumor-induced myelopoiesis. Additionally, we observed that age-associated myelopoiesis correlates with the production of IL-1 alarmins in monocytes and myeloid progenitors. Blocking this pathway with the IL1R1 inhibitor anakinra normalized myelopoiesis and promoted tumor control. However, the specific molecular mechanisms and cellular players driving age-associated pro-tumoral myelopoiesis remain unknown. In this proposal, we aim to elucidate these mechanisms through several approaches. We will conduct high-dimensional profiling of tumors from an early-stage lung cancer patient cohort, perform multi-omics phenotyping of myeloid cells and progenitors from young and aged patients as well as healthy donors, and undertake complex bone marrow experiments to isolate and characterize the impact of immune aging on age-associated inflammation. Specifically, in aim 1 we will identify the cellular players involved in the response to IL-1 signaling and define their role in age-associated inflammation and tumor progression. In aim 2, we will define the central role of DNA methyltransferase 3A in age-dependent changes in the myeloid compartment. In aim 3, we will characterize the contribution of age- associated transposable element reactivation in the myeloid compartment to age-associated inflammation. This proposal is the first to propose defining the cell-specific molecular pathways contributing to age-associated pathogenic myelopoiesis. The results of this study will enable the development of new therapeutic approaches targeting pathogenic myelopoiesis and associated inflammation in aged patients.