Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy
Year: 2020
Type: article
Study design: Observational Study
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.
DOI: 10.1093/jnci/djaa073
Authors: Theodoros Michelakos, Lei Cai, Vincenzo Villani, Francesco Sabbatino, Filippos Kontos, Carlos Fernández-del Castillo, Teppei Yamada, Azfar Neyaz, Martin S Taylor, Vikram Deshpande, Tomohiro Kurokawa, David T Ting, Motaz Qadan, Colin D Weekes, Jill N Allen, Jeffrey W Clark, Theodore S Hong, David P Ryan, Jennifer Y Wo, Andrew L Warshaw, Keith D Lillemoe, Soldano Ferrone, Cristina R Ferrone
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: IL-15 TRiKES-based specific immunotherapy of pancreatic ductal adenocarcinoma, G2507547705, T cell plasticity, fusion proteins and CAR T cell-based immunotherapy of head and neck cancer, Identification of biomarkers which is useful for predicting the efficacy and treatment selection of immune checkpoint inhibitors, G6691581647, Elucidating structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling.
OpenAlex ID: W3033893295