Abstract B077: FOLFIRINOX Bolsters the Intratumoral and Systemic B Cell Activation Compared to Gemcitabine-Abraxane in Patients with PDAC

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the world, and its poor prognosis is driven by an immunosuppressive tumor microenvironment (TME). Standard PDAC treatment combines surgical resection with perioperative chemotherapy, either Gemcitabine-Abraxane (Gem) or FOLFIRINOX (FFX). B cell infiltration and germinal center (GC) formation are linked with improved survival in solid tumors. B cells are a heterogenous population that respond to antigen stimulation and differentiate into memory B cells (MBCs) or plasma cells (PCs) via two different education pathways, a GC-associated response (GCR) and/or an extrafollicular response (EFR). The GCR occurs within tertiary lymphoid structures (TLS), ectopic lymphoid organs that arise at sites of chronic inflammation with the most functionally active TLS containing GC with follicular dendritic cells. This response produces long lived MBCs and highly specific PCs but takes several days to weeks. By contrast, the EFR is a rapid B cell activation pathway that occurs outside of GCs and generates short lived PCs within days and acts as a first line of humoral defense while the GCR develops. Together, these responses provide both immediate and durable humoral immunity but can be altered by therapeutics. Gem is cytotoxic and lymphocyte depleting, however, FFX has oxaliplatin which can induce immunogenic cell death, allowing for an increase in damage-associated molecular patterns (DAMPs) that can enhance antigen availability and presentation. We hypothesized that immunogenic cell death and DAMPs via FFX would increase B cell activation and subsequent GCR and EFR in PDAC patients. We investigated these responses via multispectral imaging of patient tumors, ex vivo phenotyping and in vitro modulation of B cells via patient derived organoids (PDOs). We analyzed TLS state and activity in primary resected tissue from either treatment naïve (TN) or patients treated with Gem or FFX. We found an increase in B and T cell proliferation in the GCR in the FFX patients compared to TN and Gem. Further, we analyzed the abundance of MBCs and ASCs in paired patient peripheral blood mononuclear cells both pre and post treatment using spectral flow cytometry. The post treatment FFX samples compared to Gem had increased ASCs and MBCs associated with the EFR and GCR. We tested the effects of the PDAC TME on naïve B cell differentiation as they begin both responses. Naïve B cells cultured with FFX conditioned media from PDOs had increased production of PCs at an earlier time point indicative of an EFR. Together, our findings demonstrate that FFX more effectively activates a robust EFR for early protection while also inducing a more durable and selective GCR response that supports prolonged antitumor immunity in PDAC. These results suggest that the type of chemotherapy regimen can shape a patient’s immune response and further supports the rationale to pair FFX based neoadjuvant therapies with B cell and TLS targeted therapeutics to improve outcomes in PDAC patients.