Distinct response to IL-1β blockade in liver- and lung-specific metastasis mouse models of pancreatic cancer with heterogeneous tumor microenvironments.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a heterogeneous tumor microenvironment (TME). The mechanism by which this heterogeneity confers resistance against immunotherapy remains unclear. Interleukin- 1β (IL-1β) is a proinflammatory cytokine that regulates heterogeneous cancer associated fibroblast (CAF) phenotype and promotes an immunosuppressive TME. Anti-IL-1β monoclonal antibody significantly enhanced the anti-tumor activity of anti-PD-1 in a preclinical model of PDAC. However, clinical trials have shown limited activity of the anti-IL-1β and anti-PD-1 combination. Therefore, we hypothesize that anti-tumor immune response to the combination of anti-IL-1β and anti-PD-1 antibodies is context-dependent and would be affected by the TME heterogeneity in PDAC.

Methods: Liver- and lung-specific metastasis mouse models of PDAC were used to investigate the antitumor activity of anti-IL-1β and anti-PD-1 antibodies alone or in combination by ultrasound examination and survival analysis. Their effects on the TME heterogeneity were assessed by flow cytometry and single nuclear RNA sequencing.

Results: The combination of anti-IL-1β and anti-PD-1 antibodies does not slow primary tumor growth but prolongs overall survival and reduces lung metastasis rates in a PDAC orthotopic murine model with lung metastasis tropism. In contrast, combination therapy slows primary tumor growth and prolongs survival, but does not reduce liver metastasis rates in a PDAC murine orthotopic model with liver metastasis tropism. Flow cytometry analysis showed that the combination of anti-IL-1β and anti-PD-1 antibodies restores T cell activation negated by the monotherapies. Mechanistically, in the PDAC model with lung metastasis tropism, but not in the model with liver metastasis tropism, combination treatment reverses an increased trend of immunosuppressive myeloid cells as a result of monotherapy. Single-nuclear RNA sequencing analysis of both organ-specific tumor models demonstrated that anti-IL-1β treatment altered infiltration and function of CAF and immune cells differently. Furthermore, anti-IL-1β treatment modulated cytokine/chemokine ligand-receptor-receptor interactions in the models with different organ-specific metastasis distinctly.

Conclusion: This study reveals the differential responses of organ-specific metastasis mouse models of PDAC with distinct TMEs to anti-IL-1β and anti-PD-1 treatments, suggesting that treatment response is context-dependent and affected by TME heterogeneity.