Tuesday, April 23, 2024
4/23/2024
Type 2 immune responses are classically associated with parasite infections at barrier surfaces, and evolved in part to repair the massive tissue damage that these maladies induce. However, the role of Type 2 immunity in cancer progression is understudied, despite the fact that many cancers occur at mucosal surfaces that are primed to engage such responses upon tissue insult. Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide. ¿PD-(L)1 immunotherapy has revolutionized care for NSCLC patients, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) which is predominantly populated by various myeloid cell subsets. Using single cell RNA-sequencing (scRNA-seq), we recently mapped the immune landscape of the human and murine NSCLC TME. We identified several newfound populations of myeloid cells that exhibited high transcriptional concordance across species. In both instances, we found that myeloid cells within the TME specifically upregulated a transcriptional program driven by IL-4, a prototypical Type 2 cytokine. Blockade of IL-4 strongly protected mice against orthotopic lung tumors. Surprisingly, we found that IL-4-producing Th2 cells were essentially absent from the lung TME in mice and humans. Instead, IL-4 was almost exclusively produced by basophils. Accordingly, antibody-mediated depletion of basophils in vivo strongly reduced lung tumor development. Using mice with cell type-specific deletion of the IL-4R¿¿ we found that granulocyte-monocyte progenitor (GMP)-derived cells were the dominant immune cells responding to IL-4 to enhance tumor burden. Within the tumor, the overwhelming majority of these cells are macrophages and neutrophils. Surprisingly, we also discovered that myeloid progenitors in BM directly sense IL-4/IL-13 signaling during lung tumor development. Furthermore, GMP-specific deletion of IL-4R¿ enhanced myeloid cell differentiation in response to lung tumors, preventing the so-called “emergency myelopoiesis” known to fuel tumor growth. Our central hypothesis is that basophil-derived IL-4 promotes NSCLC by controlling the development and function of immunosuppressive myeloid cells. To address this, we first will identify signals from neoplastic cells that activate basophils to produce IL-4 (Aim 1). Then, we will define how myeloid-intrinsic IL-4R¿ signaling controls the immune response to NSCLC, both at the level of the TME and at the level of myeloid differentiation in BM, and how these two arms synergize during ¿PD-1 immunotherapy (Aim 2). Finally, we will integrate our findings from murine systems into the first human clinical trial of dupilumab, an FDA-approved IL-4R¿ blocking antibody, in metastatic NSCLC patients who have not responded to immunotherapy and evaluate relevant immunologic alterations. Collectively, our work will (i) define a novel axis controlling lung tumor development, (ii) identify targets for therapeutic intervention, and (iii) reinforce a growing paradigm in which tumor signals instruct the fates of developing myeloid cells to affect cancer outcome.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
