Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy. (4th June 2020)

• Record Type: Journal Article
• Authors: Michelakos, Theodoros; Cai, Lei; Villani, Vincenzo; Sabbatino, Francesco; Kontos, Filippos; Fernández-del Castillo, Carlos; Yamada, Teppei; Neyaz, Azfar; Taylor, Martin S; Deshpande, Vikram; Kurokawa, Tomohiro; Ting, David T; Qadan, Motaz; Weekes, Colin D; Allen, Jill N; Clark, Jeffrey W; Hong, Theodore S; Ryan, David P; Wo, Jennifer Y; Warshaw, Andrew L; Lillemoe, Keith D; Ferrone, Soldano; Ferrone, Cristina R
• Is Part Of: Journal of the National Cancer Institute. Volume 113:Number 2(2021)
• Page Start: 182
• Page End: 191
• Publication Date: 2020-06-04
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djaa073
• Languages: English
• ISSNs: 0027-8874

Abstract

Abstract: Background: Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. Methods: Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4 +, FoxP3 +, CD8 +, granzyme B + cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided. Results: Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort ( P = .006). HLA class II expression was lowest in photon and highest in proton patients ( P = .02). The FOLFIRINOX cohort exhibited the densest CD8 + cell infiltration ( P < .001). FOLFIRINOX and proton patients had the highest CD4 + and lowest T regulatory (FoxP3 + ) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group ( P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival. Conclusions: Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8 + cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.