Abstract 5140: Combined administration of poly(I:C) and resiquimod triggers effective antitumoral response in mouse models of pancreatic adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies worldwide. The lack of clinical symptoms in the early stages of the disease and the poor immunogenicity of PDAC are two major causes of late diagnosis and inefficient therapies. The tumor microenvironment of PDAC is rich in stromal cells inducing desmoplasia, complicating the arrival of medical compounds, as well as in immune cells, that are suppressed by several mediators produced by cancer cells. In this setting, it has been shown that some medications can restore the antitumoral activity of innate immune cells that, in turn, re-activate also adaptive immune cells. In this study, we present the combination of the TLR agonists poly(I:C) (pIC - TLR3) and resiquimod (R848 - TLR7/8) as an immunotherapeutic tool in PDAC. In a subcutaneous model of PDAC (K8484 cells, isolated from KPC mice that spontaneously develop PDAC and recapitulate the features of human pancreatic cancer), the intratumoral administration of pIC+R848 for 5 times every 2-3 days led to the complete regression of the tumor in 100% of the treated mice. Moreover, all mice were protected from a second and a third rechallenge with the same cell line, performed months after the first treatments. Mechanistic studies performed on the tumors with flow cytometry demonstrated an increase of MHC-II positive cells in the monocytic (Ly6C+) compartment, as well as an increase in the number of mature CD8+ T cells and NK cells. Similar findings were demonstrated also in another heterotopic model obtained injecting Panc02 cells, another cell line with a sarcomatous phenotype. Consistently with the flow cytometry data, the depletion of CD4+ and CD8+ T cells abolished the antitumoral efficacy of pIC+R848, while the depletion of NK cells and CSF-1R+ cells was not sufficient to abolish the antitumoral response, suggesting a strong involvement of the adaptive immunity. In line with these findings, the intratumoral administration of pIC+R848 in mice unable to produce IFN-γ failed to reduce the tumor growth. In conclusion, our work clearly demonstrates that pIC+R848 are an effective treatment for PDAC when injected intratumorally and that this activity strongly relies on IFN-γ and adaptive immunity. Further investigations are ongoing to assess their potential in orthotopic models using different routes of administration, in a setting closer to the real clinical situation. Citation Format: Aldo Ummarino, Clément Anfray, Andrea Mariancini, Domenico Supino, Cecilia Garlanda, Fernando Torres Andòn, Alberto Mantovani, Paola Allavena. Combined administration of poly(I:C) and resiquimod triggers effective antitumoral response in mouse models of pancreatic adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5140.