Abstract C020: Neutrophil-mediated stromal-tumor IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study

Abstract

Abstract Background: Partial/complete pathologic response following neoadjuvant chemotherapy (NAC) in pancreatic cancer (PDAC) patients undergoing pancreatectomy is associated with improved survival. We sought to determine whether neutrophil-to-lymphocyte ratio (NLR) dynamics predict pathologic response following chemotherapy in PDAC, and if manipulating NLR impacts chemosensitivity in preclinical models and uncovers potential mechanistic underpinnings underlying these effects. Methods: Pathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent (case-cohort design). Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils÷%lymphocytes) or NLR dynamics during chemotherapy (ΔNLR=pre-surgery—pre-chemotherapy NLR) and pathologic response, disease-free survival (DFS), and overall survival (OS). To preclinically model effects of NLR attenuation on chemosensitivity, C57BL/6 mice (n=8-10/arm) were orthotopically injected with KrasG12D/+;Trp53fl/+;PdxCre(KPC) cells and randomized to vehicle, NLR-attenuating anti-Ly6G, gemcitabine/paclitaxel, or gemcitabine/paclitaxel+anti-Ly6G treatments. Results: In 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (P<0.001) and ΔNLR attenuation during NAC (P=0.002) were independently associated with partial/complete pathologic response. An NLR score=pre-chemotherapy NLR+ΔNLR correlated with DFS (P=0.006) and OS (P=0.002). Upon preclinical modeling, combining NLR-attenuating anti-Ly6G treatment with gemcitabine/paclitaxel—compared with gemcitabine/paclitaxel or anti-Ly6G alone—not only significantly reduced tumor burden and metastatic outgrowth, but also augmented tumor-infiltrating CD107a+-degranulating CD8+ T-cells (P<0.01) while dampening inflammatory cancer-associated fibroblast (CAF) polarization (P=0.006) and chemoresistant IL-6/STAT-3 signaling in vivo. Neutrophil-derived IL-1β emerged as a novel mediator of stromal inflammation, inducing inflammatory CAF polarization and CAF-tumor cell IL-6/STAT-3 signaling in ex vivo co-cultures. Conclusions: Therapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC. Citation Format: Iago De Castro Silva, Anna Bianchi, Nilesh Deshpande, Prateek Sharma, Siddharth Mehra, Peter Hosein, Deukwoo Kwon, Nipun Merchant, Jashodeep Datta. Neutrophil-mediated stromal-tumor IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C020.