%0 Journal Article %A Carmine Carbone %A Geny Piro %A Antonio Agostini %A Pietro Delfino %A Francesco De Sanctis %A Vincenzo Nasca %A Francesco Spallotta %A Claudio Sette %A Maurizio Martini %A Stefano Ugel %A Vincenzo Corbo %A Paola Cappello %A Emilio Bria %A Aldo Scarpa %A Giampaolo Tortora %T Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer %D 2021 %R 10.1136/jitc-2021-002876 %J Journal for ImmunoTherapy of Cancer %P e002876 %V 9 %N 9 %X Background Complex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity.Methods We generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis.Results We demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes.Conclusion We demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting.All data relevant to the study are included in the article or uploaded as supplemental information. All methodologies, analyses, and results are included in the article. %U https://jitc.bmj.com/content/jitc/9/9/e002876.full.pdf