The role of CXCR1/2 dual inhibitor ladarixin on tumor burden and immunotherapy response in pancreatic cancer.
Authors: Tortora Giampaolo , Piro Geny , Carbone Carmine , Agostini Antonio , Esposito Annachiara , DePizzol Maria , Novelli Rubina , Gavioli Elizabeth Marie , Allegretti Marcello , Aramini Andrea , Caggiano Alessia , Granitto Alessia , De Sanctis Francesco , Ugel Stefano , Corbo Vincenzo , Martini Maurizio , Lawlor Rita Teresa , Scarpa Aldo 
Published: June 2022

e16304

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies for which few effective pharmacological treatments are currently available. Immunotherapy has revolutionized the treatment of several solid tumors, yet the results obtained in PDAC have been disappointing. Although PDAC is generally considered an immune “cold” cancer, different PDAC subtypes have diverse immune tissue microenvironment (TME) components, including tumor-associated macrophages (TAMs), that might differentially influence immunotherapy responsiveness and patient survival. TAM population is plastic, switching rapidly from a pro- to an anti-tumoral behaviour, based on specific cytokines in TME. A role for the chemokines/CXCR axis in inducing M1 polarization has been proposed in several tumors, and, consequently, the potential advantage of combining CXCR inhibitors with immune check-point inhibitors. Here, we evaluated the effectiveness of the CXCR1/2 inhibitor ladarixin, alone or in combination with anti-PD-1, on immune tolerance against PDAC and on tumor growth. Methods: A set of preclinical models were obtained by engrafting mouse PDAC-derived cell lines into the pancreas of recipient syngeneic immune-competent mice, as well as by orthotopically transplanting patient derived PDAC tumor into human immune system reconstituted (HIR) mice (Hu-NSG-CD34+). Tumor bearing mice were randomly assigned to receive vehicles, ladarixin, and anti-PD-1 alone or in combination with ladarixin, to evaluate the effect of treatment on tumor growth and mice survival. This work is supported by AIRC and Italian Ministry of Health grants. Results: CXCR1/2 inhibition by ladarixin reverted in vitro tumor-mediated M2 polarization and migration of Bone Marrow-Derived Macrophages. Ladarixin as a single agent significantly reduced tumor burden in cancer derived graft (CDG) models with high-immunogenic potential and significantly increased the efficacy of ICI in non-immunogenic CDG models that did not respond to anti-PD-1 treatment. In a HIR mouse model bearing the immunogenic subtype of human PDAC, ladarixin showed high efficacy as a single agent and the ability to increase the antitumor effects of anti-PD-1 with a statistically significant reduction of tumor volume compared to control and to single treatments (ctr vs lad, p = 0.0077; ctr vs comb, p = 0.0098; lad vs comb: 0.002; anti-PD-1 vs comb, p = 0.036). Moreover, ladarixin both as monotherapy and in combination setting increased survival (median survival: ctr 49.5 vs lad 74.5 days, p = 0.044; ctr 49.5 vs comb 150 days, p = 0.0108; anti-PD-1 57 vs comb 150 days, p = 0.046; lad 74.5 vs comb 150 days, p = 0.047). Conclusions: Ladarixin in combination with anti-PD-1 might represent an effective approach for the treatment of PDAC, converting a protumoral into an immunopermissive microenvironment in PDAC subtypes usually refractory to immunotherapy.