Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy

Abstract

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.

Pancreatic Cancer and Immunotherapy: A Clinical Overview

“…Recently, results from the phase 2a COMBAT trial suggested that chemotherapy concurrent with combined anti-PD-1 and anti-C-X-C motif chemokine receptor (CXCR)4 may augment chemotherapeutic effects after attaining an mOS of 7.8 months from the start of immunotherapy in pre-treated mPDAC patients [49]. Results from both trials are in line with the expanding recognition that cytotoxic drugs (i.e., chemotherapy) can enhance immunotherapeutic effects by stimulating immunogenic tumor cell death, reducing tumor-induced immune suppression and increasing effector T cell function and infiltration [53][54][55]. Definitive advice regarding combined treatment with chemotherapy (gemcitabine/paclitaxel or FOLFIRINOX) and anti-PD-1 may be provided by two large RCTs (ClinicalTrials.gov Identifier: NCT04674956; NCT03983057).…”

The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types

“…In conclusion, crude measurement of the tumour stroma content might be insufficient for the purpose of prognostication, and it is likely that other stromal qualities, including mechanical features, extracellular matrix components or immune cell composition have overriding importance in the tumorigenic process [ 6 , [32] , [33] , [34] ]. Nevertheless, we believe that our comprehensive analysis contributes, on an elementary level, with novel perspectives on the tumour-stroma interaction and serves as a strong starting point for further focused studies aimed at elucidating the role of the tumour stroma fraction in cancer.…”

microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3

“…Isolation and identification of EVs: miR-21-5p is upregulated in M2 macrophage-derived EVs Infiltration of M2 macrophages is closely connected with the inferior prognosis of PaCa (Michelakos et al 2020), and M2 macrophage-derived EVs can promote the functions of PaCa cells (Yin et al 2020). In the experiment, THP-1 cells were induced to polarize into M2 macrophages, which were elliptical and grew aggregately ( Fig.…”