P1081 - Longitudinal Immunoprofiling of Pancreatic Cancer Patients to Identify Mediators of Therapy Resistance

Eileen Carpenter, MD, PhD¹, Samantha Kemp, PhD², Padma Kadiyala, ¹, Nina Steele, PhD¹, Ahmed Elhossiny, ¹, Veerin Sirihorachai, ¹, Wenting Du, PhD¹, Carlos Espinoza, MA¹, Stephanie The, MA¹, Julia Freeman, ¹, Sean Bhalla, MD¹, Ajay Singhvi, MD¹, Michelle Anderson, MD, MSc¹, Richard Kwon, MD¹, Erik-Jan Wamsteker, MD¹, Anoop Prabhu, MD¹, Allison Schulman, MD¹, Valerie Gunchick, MA¹, Vaibhav Sahai, MD¹, Timothy Frankel, MD¹, Filip Bednar, MD, PhD¹, Marina Pasca Di Magliano, PhD^1
1University of Michigan, Ann Arbor, MI; ²University of Pennsylvania, Philadelphia, PA

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the 4^th leading cause of cancer-related death in the US. Although pancreatic cancer cells show susceptibility to standard chemotherapeutic agents, most patients eventually develop resistance, leading to poor survival. There is thus an urgent need to understand how pancreatic cancer cells become resistant to standard therapies. A large body of work using murine models implicate the myeloid compartment of the immune microenvironment playing a role in therapy resistance, yet longitudinal human studies remain scarce. To study the effect of chemotherapy on the systemic immune response of PDAC patients, we performed high resolution immune profiling of 30 PDAC patients longitudinally over the course of their treatment.

Methods: Patients were consented according to IRB HUM00025339 for longitudinal blood collection. Peripheral blood mononuclear cells (PBMCs) were isolated from blood and profiled using single cell RNA sequencing and mass cytometry with a custom tailored immune panel to profile the immune landscape at the single-cell RNA and protein level, respectively. Data were analyzed using the Seurat pipeline and the Cytobank platform.

Results: We performed mass cytometry on longitudinally matched PBMCs from 30 patients and single cell RNA sequencing on 6 patients in the treatment naïve and on treatment state. Mass cytometry revealed distinct alterations in the myeloid population, with a shift toward CXCR2^hiPD-L1^hi granulocytes with FOLFIRINOX treatment over time (Fig1A). Analysis of PBMCs at the single cell level shows a distinct myeloid signature with FOLFIRINOX and in particular highlights interleukin-8, a chemokine involved in myeloid cell chemotaxis that is associated with poor prognosis in pancreatic cancer (Fig1B).

Discussion: Longitudinal sampling of patient blood reveals a shift in the immunosuppressive myeloid population with chemotherapy, and further studies show a myeloid signature of genes associated with treatment. Going forward, we will extend our pipeline to include analysis of tumor tissue before and after chemotherapy, leveraging endoscopic fine needle biopsies both at initial tissue diagnosis and again after chemotherapy at fiducial marker placement for patients in whom radiation treatment is indicated. These studies will allow for a rigorous study of the changes in the local and systemic immune system that characterize this deadly disease, and will provide information on how to leverage these changes to overcome therapy resistance.



Disclosures:


Eileen Carpenter, MD, PhD¹, Samantha Kemp, PhD², Padma Kadiyala, ¹, Nina Steele, PhD¹, Ahmed Elhossiny, ¹, Veerin Sirihorachai, ¹, Wenting Du, PhD¹, Carlos Espinoza, MA¹, Stephanie The, MA¹, Julia Freeman, ¹, Sean Bhalla, MD¹, Ajay Singhvi, MD¹, Michelle Anderson, MD, MSc¹, Richard Kwon, MD¹, Erik-Jan Wamsteker, MD¹, Anoop Prabhu, MD¹, Allison Schulman, MD¹, Valerie Gunchick, MA¹, Vaibhav Sahai, MD¹, Timothy Frankel, MD¹, Filip Bednar, MD, PhD¹, Marina Pasca Di Magliano, PhD¹. P1081 - Longitudinal Immunoprofiling of Pancreatic Cancer Patients to Identify Mediators of Therapy Resistance, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.