Nasal administration of recombinantNeospora caninumsecreting IL-15/IL-15Rα inhibits metastatic melanoma development in lung

Abstract

BackgroundMetastases are the leading cause of mortality in many cancer types and lungs are one of the most common sites of metastasis alongside the liver, brain, and bones. In melanoma, 85% of late-stage patients harbor lung metastases. A local administration could enhance the targeting of metastases while limiting the systemic cytotoxicity. Therefore, intranasal administration of immunotherapeutic agents seems to be a promising approach to preferentially target lung metastases and decrease their burden on cancer mortality. From observations that certain microorganisms induce an acute infection of the tumor microenvironment leading to a local reactivating immune response, microbial-mediated immunotherapy is a next-generation field of investigation in which immunotherapies are engineered to overcome immune surveillance and escape from microenvironmental cancer defenses.MethodsThe goal of our study is to evaluate the potential of the intranasal administration ofNeospora caninumin a syngeneic C57BL6 mouse model of B16F10 melanoma lung metastases. It also compares the antitumoral properties of a wild-typeN. caninumversusN. caninumsecreting human interleukin (IL)-15 fused to the sushi domain of the IL-15 receptor α chain, a potent activator of cellular immune responses.ResultsThe treatment of murine lung metastases by intranasal administration of anN. caninumengineered to secrete human IL-15 impairs lung metastases from further progression with only 0,08% of lung surface harboring metastases versus 4,4% in wild-typeN. caninumtreated mice and 36% in untreated mice. The control of tumor development is associated with a strong increase in numbers, within the lung, of natural killer cells, CD8+T cells and macrophages, up to twofold, fivefold and sixfold, respectively. Analysis of expression levels of CD86 and CD206 on macrophages surface revealed a polarization of these macrophages towards an antitumoral M1 phenotype.ConclusionAdministration of IL-15/IL-15Rα-secretingN. caninumthrough intranasal administration, a non-invasive route, lend further support toN. caninum-demonstrated clear potential as an effective and safe immunotherapeutic approach for the treatment of metastatic solid cancers, whose existing therapeutic options are scarce. Combination of this armed protozoa with an intranasal route could reinforce the existing therapeutic arsenal against cancer and narrow the spectrum of incurable cancers.