Tumor microenvironment immune response in pancreatic ductal adenocarcinoma patients treated with neoadjuvant therapy
Menée à partir de données clinicopathologiques portant sur 248 patient atteints d'un adénocarcinome canalaire du pancréas (âge médian : 64 ans), cette étude évalue l'effet d'un traitement néoadjuvant de type FOLFIRINOX en combinaison ou non avec une chimioradiothérapie sur la réponse immunitaire du microenvironnement tumoral
Background : Neoadjuvant FOLFIRINOX and chemoradiation have been utilized 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 : Clinicopathologic variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with/without chemoradiation, proton chemoradiation (25Gy), photon chemoradiation (50.4Gy) or no neoadjuvant therapy. 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 two-sided.
Results : Two hundred forty-eight PDAC patients were included. Median age was 64y; 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 OS.
Conclusions : Neoadjuvant FOLFIRINOX with/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.
Journal of the National Cancer Institute , résumé, 2019