Background The efficacy of chimeric antigen receptor (CAR) T cells against solid tumors remains unsatisfactory due to impaired trafficking of the CAR T cells into the tumor microenvironment (TME) and the presence of immunosuppressive factors and cells. 5’- triphosphate double-stranded RNA (3p-RNA) is recognized by the intracellular pattern recognition receptor retinoic acid-induced gene I (RIG-I). RIG-I activates a downstream signaling cascade, triggering the expression of type I interferons (IFN), proinflammatory cytokines and chemokines enhancing immune surveillance in the TME. We hypothesized that priming the TME with RIG-I ligands increases the efficacy of CAR T cell therapy.
Materials and Methods T110299 pancreatic tumor cells (derived from a genetically-engineered Kras and p53 mutant murine PDAC model) were engineered to express murine epithelial cell adhesion molecule (EpCAM) and used to induce subcutaneous or orthotopic tumors in C57BL/6J female mice. Mice bearing T110299 EpCAM+ tumors were treated with intratumoral or i.v. injections of 3p-RNA followed by i.v. injection of syngeneic murine T cells that were retrovirally tranduced to express anti-EpCAM CARs. Three days after CAR T cell injection, immune cell composition and CAR T cell infiltration in the TME were assessed by flow cytometry. Additionally, tumor growth and survival were monitored.
Results Intratumoral injections of 3p-RNA reshaped the myeloid immune compartment in the TME by significantly reducing suppressive polymorphonuclear-MDSC and macrophages while increasing Ly6Chigh inflammatory monocytes. Moreover, antigen-presenting cells, such as dendritic cells and macrophages, were activated as evidenced by increased MHC-I expression levels. This was paralleled by a significant increase in the infiltration of CAR T cells into the TME in the combination therapy group. Interestingly, anti-EpCAM CAR T cells alone failed to control the tumor growth of T110299 EpCAM+ tumors, while monotherapy with 3p-RNA slightly delayed tumor growth in the subcutaneous model. Combination of 3p-RNA with anti-EpCAM CAR T cells induced a significant clinical benefit with tumor regression in 50% of the treated mice in the subcutaneous tumor model and prolonged survival in an orthotopic model.
Conclusions Remodeling the immunosuppressive TME using RIG-I ligands is a promising strategy for overcoming therapeutic resistance of CAR T cells in solid tumors, such as pancreatic cancer.
Funding The project was supported by the international doctoral program ‘i-Target: Immunotargeting of cancer’ funded by the Elite Network of Bavaria and the Stiftungen zu Gunsten der Medizinischen Fakultät.
Disclosure Information A.M. Senz: None. S.L. Formisano: None. B. Cadilha: None. T. Lorenzini: None. S. Endres: None. S. Kobold: None. M. Schnurr: None. L.M. König: None.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.