Gemcitabine Plus Nab-Paclitaxel Induces PD-L1 mRNA Expression in Plasma-Derived Microvesicles in Pancreatic Cancer

SIMPLE SUMMARY: There is an urgent need to improve the therapeutic options in pancreatic cancer. In this study, we assessed the ability of two standard-of-care chemotherapeutic regimens to modulate the levels of PD-L1 mRNA isolated from plasma-derived microvesicles (MVs) of patients with pancreatic cancer. Our findings demonstrate for the first time a statistically significant difference in MV-derived PD-L1 mRNA levels at 3 months vs. baseline in patients treated with GEMnPAC, compared to those receiving FOLFIRINOX. Although these findings need to be confirmed in larger prospective cohorts, they can represent a rational basis for testing the hypothesis that the GEMnPAC schedule may be used as an immunotherapy-modulating regimen in PDAC patients due to its capability of increasing PD-L1 mRNA expression. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a non-immunogenic tumor poorly responsive to immune checkpoint inhibitors. This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients. Plasma was collected before starting chemotherapy and after 3 months of treatment. mRNA was extracted from MVs, and PD-L1 expression was measured by digital droplet PCR. Twenty-eight patients were PD-L1 positive in MVs at baseline, of which 18 were in the GEMnPAC cohort and 10 in the FOLFIRINOX one. The amount of PD-L1 expression in MVs increased from baseline to 3 months of treatment in patients receiving GEMnPAC (median value 0.002 vs. 0.005; p = 0.01) compared to those treated with FOLFIRINOX (median 0.003 vs. 0.004; p = 0.97). The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD: p = 0.08; PD: p = 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients.