Deconstructing pathogenic myelopoiesis in cancer immunosuppression and treatment resistance

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY A major barrier for treating solid tumors are myeloid cells such as monocytes, macrophages, and neutrophils with diverse immunoregulatory functions in the tumor microenvironment (TME). These cells are mostly derived from hematopoietic-origin precursors in the bone marrow (BM) and expand in the TME due to tumor-driven myelopoiesis. This atypical expansion of myeloid lineage provides a steady supply of pathogenic mono- macrophages in the TME and contributes to immunosuppression as well as therapy resistance. Future myeloid-targeting immunotherapies will need to target this tumor-BM axis and limit pathogenic myelopoiesis to durably reshape the TME and enable anti-tumor activity. To do so, we need a clearer understanding of genetic and epigenetic changes that occur in BM myeloid progenitors upon tumor inflammation that ultimately influences their survival, mobilization, and metabolism. My K99 proposal addresses this important question and aims to study the epigenetic regulation and priming of key regulatory pathways in tumor-educated BM myeloid progenitors. My postdoctoral work has demonstrated that activation of the NRF2 oxidative stress response is an important maladaptation in cancer-infiltrating macrophages, driving pro-survival pathways to sustain immunosuppressive activity in the TME. Based on exciting preliminary data in mouse and human, I hypothesize that tumors influence the chromatin state of BM myeloid progenitors, priming NRF2 activity to rewire metabolism, poise cytoprotection, and limit inflammatory gene activation. As part of my K99 proposal, I will assess how NRF2 influences chromatin loci in tumor-educated BM progenitors (Aim 1A) and effects metabolic adaptations (Aim 1B), using chromatin assays such as CUT&RUN and ATAC sequencing with functional metabolic readouts via probe-based cytometry. These studies lay the groundwork for my R00-phase work on the regulation of reactive myelopoiesis in response to chemotherapy. Clinicians have long recognized that cytotoxic chemotherapies severely impact BM and drive a myeloid-biased rebound linked to treatment resistance and tumor relapse. I seek to understand the long-term changes triggered by chemotherapy-induced oxidative stress and what role the resultant myeloid expansion plays in tumor immune escape and therapy resistance. In my R00, I will establish an independent program around reactive myelopoiesis in cancer therapy resistance, initially focusing on the role played by oxidative stress in chemotherapy-induced myeloid rebound in pancreatic cancer (Aim 2). I will utilize longitudinal biospecimens from pancreatic cancer (PDAC) patients undergoing standard-of-care chemotherapy to interrogate oxidative stress response using targeted cytometry and chromatin. I will exploit mouse models of chemo-refractory PDAC to study the specific contribution of BM oxidative stress to relapse. Building on my research plan, resources, training, and advisory expertise at Mount Sinai, I will advance the field of tumor-associated myelopoiesis and help develop better, more durable myeloid- targeting immunotherapy strategies that work in synergy with existing therapies for cancers such as PDAC.