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.
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.
Authors: Bradley N Mills; Haoming Qiu; Michael G Drage; Chunmo Chen; Jocelyn S Mathew; Jesse Garrett-Larsen; Jian Ye; Taylor P Uccello; Joseph D Murphy; Brian A Belt; Edith M Lord; Alan W Katz; David C Linehan; Scott A Gerber Journal: Clin Cancer Res Date: 2021-12-03 Impact factor: 13.801
Authors: Florentine E F Timmer; Bart Geboers; Sanne Nieuwenhuizen; Evelien A C Schouten; Madelon Dijkstra; Jan J J de Vries; M Petrousjka van den Tol; Tanja D de Gruijl; Hester J Scheffer; Martijn R Meijerink Journal: Curr Oncol Rep Date: 2021-04-17 Impact factor: 5.075
Authors: Patrick Micke; Carina Strell; Johanna Mattsson; Alfonso Martín-Bernabé; Hans Brunnström; Jutta Huvila; Malin Sund; Fredrik Wärnberg; Fredrik Ponten; Bengt Glimelius; Ina Hrynchyk; Siarhei Mauchanski; Salome Khelashvili; Gemma Garcia-Vicién; David G Molleví; Per-Henrik Edqvist; Aine O Reilly; Sara Corvigno; Hanna Dahlstrand; Johan Botling; Ulrika Segersten; Agnieszka Krzyzanowska; Anders Bjartell; Jacob Elebro; Margareta Heby; Sebastian Lundgren; Charlotta Hedner; David Borg; Jenny Brändstedt; Hanna Sartor; Per-Uno Malmström; Martin Johansson; Björn Nodin; Max Backman; Cecilia Lindskog; Karin Jirström; Artur Mezheyeuski Journal: EBioMedicine Date: 2021-03-08 Impact factor: 8.143