Modulation of the human pancreatic microenvironment by combined cytokine and immune checkpoint blockade

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PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) harbors significant barriers restraining immunity. One notable factor is the fibrotic stroma, driven by cancer associated fibroblast (CAF) subsets. Another is the myeloid-skewed immune composition of TIL in PDAC tumors, which lack robust effector T cell infiltration. We postulate that interleukin-6 (IL-6) is a critical factor that promotes inflammatory CAF, enables suppressive myeloid cell residence, along with T cell dysfunction in PDAC. Using innovative translational approaches and patient specimens, we will address relationships between IL-6, CAF and the balance of myeloid and T cells in metastatic human PDAC. Studies in pre-clinical models support a role for these factors in both primary and metastatic PDAC tumors, and our work will invigorate further discovery by studying tumor and blood samples from patients where IL-6, a key cytokine mediator, is blocked along with the PD-1 immune checkpoint. This data will enhance our understanding of how CAF interact with cytokines and immune cells in metastatic foci. This proposal addresses the scientific premise that IL-6 acting directly on CAF and immune cells are key mechanisms for maintaining an immunologically “cold” tumor microenvironment (TME) in metastatic PDAC and contributes to immunotherapy resistance. We will test our overall hypothesis that IL-6 restrains immunity against PDAC, through its effects on CAF and immune cells, and that targeting it reprograms the TME to enhance efficacy of immunotherapy. Prior publications from our group have demonstrated a role for IL-6 in PDAC and shown in mouse models how targeting it can improve efficacy of immune checkpoint blockade. These extensive efforts have culminated in this proposal, which will translate into patients a first-in-human trial of IL-6 and PD-1 blockade in PDAC. This trial provides a needed study of how IL-6 and CAF are related to balance of immune cells in metastatic tumors. This proposal represents an important opportunity to uncover connections between CAF, immune cells and IL-6 in metastatic disease in patients. We will conduct two specific aims. First, we will determine how dual blockade of IL-6 and PD-1 orchestrates the balance of CAF populations in tumors from metastatic PDAC patients. In this aim, we will generate foundational data using human samples from paired pre- and on-treatment biopsies of PDAC metastases from the clinical trial. Composition of CAF will be measured via multiplex immunofluorescence (IF) to uncover how therapy modulates fibroblast subsets in metastatic PDAC. Second, we will determine how targeting IL-6 and PD-1 influences the balance of T and myeloid cells in metastatic PDAC tumors and systemic circulation. We will utilize single cell mass cytometry approaches on paired biopsies and blood to study immune phenotype reprogramming in metastases and systemic longitudinal changes during treatment and relationship to clinical response. This study will impact our understanding of how immunotherapy can be improved and provide a rich dataset related to both stroma and immune markers in metastatic PDAC to facilitate subsequent treatment opportunities.