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.