Deconstructing pathogenic myelopoiesis in cancer immunosuppression and treatment resistance

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY A major barrier for treating solid tumors are monocytes and macrophages with diverse immunoregulatory functions in the tumor microenvironment (TME). These myeloid cells are derived from hematopoietic-origin in the bone marrow (BM) and expand in the TME due to tumor-driven myelopoiesis, contributing to immunosuppression as well as therapy resistance. Myeloid-targeting immunotherapies of the future will need to target this tumor-BM axis and control myelopoiesis to durably restore anti-tumor activity in TME. 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 mobilization and metabolism. My postdoctoral work has demonstrated that activation of NRF2 oxidative stress response is an important maladaptation in TME-infiltrating macrophages, driving pro-survival pathways and immunosuppressive activity. My K99-phase work focused on the epigenetic regulation and priming of key regulatory pathways in tumor-educated BM myeloid progenitors that fuel macrophages in TME. As part of my K99, I assessed how NRF2 influences chromatin loci and metabolic maladaptation in tumor-educated BM progenitors, assessing histone poising using CUT&RUN and functional metabolic readouts via probe-based cytometry. These studies lay the groundwork for my R00-phase work on the regulation of NRF2-dependent reactive myelopoiesis in response to chemotherapy. Clinicians have long recognized that cytotoxic chemotherapies severely impact BM and drive a myeloid-biased rebound. I seek to understand the long-term changes triggered by therapy-induced oxidative stress in BM, and what role the resultant myeloid expansion plays in tumor immune escape and therapy resistance. In my independent program, we will focus on the role played by oxidative stress during chemotherapy-induced myeloid infiltration in pancreatic cancer (PDAC). I will utilize longitudinal biospecimens from patients with PDAC undergoing standard-of-care chemotherapy to interrogate oxidative stress response using targeted cytometry and chromatin assays. Furthermore, I will exploit mouse models of chemo-refractory PDAC to study the specific contribution of BM stress on relapse or metastases. We will rely on vertebrate models since de novo interactions between systemic host immunity and solid tumors can only be best captured in an intact whole-body setting with complexity that cannot be currently captured by in vitro or computational methods. Our mouse models have an extensively characterized immune system that resembles human biology, and several molecular tools available. Building on my resources, training, and advisory expertise, my program will help advance the field of tumor-associated myelopoiesis and develop more durable myeloid-targeting immunotherapy strategies that work in synergy with existing therapies for cancers such as PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Bone marrow-originating myeloid cells are often responsible for immunosuppression in cancer tissue, frequently being associated with treatment resistance and cancer relapse. This proposal aims to understand the genetic, epigenetic, and metabolic changes that occur in bone marrow myeloid cell precursors due to tumor inflammation. This proposal will also establish an independent program studying mechanisms by which bone marrow precursors are epigenetically distorted during therapy and, in turn, impact therapy resistance and cancer relapse.