Abstract 2678: Tumoral CXCR4 and CXCL12 but not CXCR7 nor PD-L1 expression predicts disease free survival (DFS) and cancer specific survival (CSS) in resected pancreatic adenocarcinoma patients
Authors: D'Alterio Crescenzo , Giardino Alessandro , Scogmaliglio Giosuè , Tatangelo Fabiana , Butturini Giovanni , Portella Luigi , Guardascione Giuseppe , Frigerio Isabella , Gobbo Stefano , Botti Gerardo , Scala Stefania 
Published: July 2021

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumor types and the 4th leading cause of tumor-related mortality in developed nations. PDAC is characterized by a highly fibrotic stroma that can physically exclude cytotoxic T cells from the vicinity of tumor cells. Targeting the axis CXCR4-CXCL12 improved T cell access to PDAC Tumor Microenvironment (TME) making tumors more susceptible to anti-PD-1/anti PD-L1 therapy. With the intent to evaluate the role of the entire CXCR4-CXCL12-CXCR7 axis in a context of PD-1/PD-L1 expression, 80 primary pancreatic cancers were evaluated in cancer cells and TME.
Methods: 80 primary PDAC samples from patients undergone surgery collected at Ospedale P. Pederzoli Peschiera del Garda (Verona, Italy) were included in the study. Immunohistochemistry was conducted using primary antibodies: Anti-CXCR7/RDC-1 clone 11G8; Anti-CXCL12 Clone #79018; two commercial anti-CXCR4 clones #44716 and the UMB-2; two commercial anti-PD-L1, clone E1L3N and 22C3.
Results: CXCR4 was expressed in 53 out of 73 tumors (72.6%). CXCL12 was predominantly identified into the membrane of cancer cells in 16 out of 75 (21.3%) tumors. CXCR7 staining was detectable in 44 out of 76 (57.8%) tumors. PD-L1 identified into the membrane of cancer cells in 35 out of 70 (50%) tumors. Patients with high CXCR4 tumor expression experienced worse outcome (DFS: 11.77 vs 22.85 months p=0.0071; CSS: 21.83 vs 35 months p&gt;0.05, not significant) and predicted short DFS in R0 patients subgroup (n=48) (DFS: 11.20 months vs 33.40 months p=0.0140). CXCL12 expression predicted DFS (p=0.0002) and CSS (p=0.0046). Of note CXCL12 predicted short DFS (p=0.0015) and CSS (p=0.0213) in R0 patient's subgroup (n=48). Although stromal expression of CXCR4, CXCL12 and CXCR7 were not prognostic, CXCR4 positive inflammatory cells and tumoral CXCL12 significantly and directly correlated with the vascular invasion. Neither tumoral nor stromal expression of PD-L1 was prognostic but PD-L1 interestingly stained the perineural invasion and tumor-infiltrating inflammatory cells of body or tail tumors. In multivariate analysis, tumoral CXCR4 expression (p=0.0043), perineural invasion (p=0.0030) and AJCC lymph node status (p=0.0016) were independent prognostic factors for DFS. Tumoral CXCL12 expression (p=0.01467), AJCC Stage (p=0.0004) and perineural infiltration (p=0.03164) were independent prognostic factors for CSS.
Conclusion: Tumoral CXCR4 and CXCL12 were prognostic factors at the univariate and multivariate analysis as for DFS and CSS in PDAC. Stromal PD-L1 stained perineural infiltration and stromal CXCR4 characterized inflammatory cells in the vascular invasion. Thus tumoral and stromal characterization for CXCR4 and CXCL12 in PDAC is worth to identify prognostic categories and to orient therapeutic approach.
Citation Format: Crescenzo D'Alterio, Alessandro Giardino, Giosuè Scogmaliglio, Fabiana Tatangelo, Giovanni Butturini, Luigi Portella, Giuseppe Guardascione, Isabella Frigerio, Stefano Gobbo, Gerardo Botti, Stefania Scala. Tumoral CXCR4 and CXCL12 but not CXCR7 nor PD-L1 expression predicts disease free survival (DFS) and cancer specific survival (CSS) in resected pancreatic adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2678.