Dendritic cell expansion and activation enhances the adaptive immune response against TNBC brain metastases

Abstract

Abstract Despite initial control by chemotherapy, Triple Negative Breast Cancer (TNBC) quickly acquires resistance and metastasizes to distal organs, including the brain. Median survival following diagnosis of TNBC brain metastases is a meager 7.3 months—indicative of a substantial unmet clinical need, with only a small subpopulation responding to checkpoint immunotherapy. As suboptimal antigen presentation can contribute to the weak T lymphocyte response to intracranial tumors, we hypothesized that enhancing dendritic cell (DC) presence in tumors may support intracranial T cell responses to tumors. Using a murine model of intracranial metastasis, we assessed immune cell frequency and function and in vivocytokine staining for flow cytometry to test whether Flt3L can be used to promote DC presence within tumors, and whether the addition of polyIC further enhances subsequent T cell responses. Flt3L treatment effectively increases the number of DC within the brains and meninges of mice, however these newly expanded populations exhibit lower proportions of the costimulatory molecule CD86 than the untreated control group, indicative of an immature phenotype. 24 hours after polyIC treatment, a higher percentage of DCs in brain tumors express CD86 but do not produce IL-12. Despite the lack of intratumoral IL-12, the combination of Flt3L and polyIC treatments led to a higher presence of T cells within tumors and their production of IFN-γ in the TME than either treatment alone. In conclusion, simply increasing the presence of DC within intracranial tumors is insufficient to promote T cell immunity; rather, deliberate activation of de novo DC is required for this full effect. Supported by grants from NIH (2T32CA009109-46 and 1R21CA226607-01A1) and the Schiff Foundation