Decoding the impact of germline and somatic genetic variation on anti-tumoral immunity and immunotherapy efficacy in brain metastatic tumors

Brain metastases (BrMs) are the most common brain tumors in adults, often originating from primary lung, breast and melanoma cancers. It is estimated that 20-40% of all cancer patients will develop metastases to the brain. Patients with BrMs present a dismal prognosis and there is an urgent need for more effective treatments. In this regard, the standard of care has been recently expanded to include molecularly targeted therapies and immunotherapies; and the genetic profile ofprimary tumors is now used to guide personalized treatment decisions for patients with lung- and melanoma-BrMs. While
immune checkpoint blockade (ICB) has shown encouraging initial outcomes in these patients, a substantial proportion of BrMs remain unresponsive to ICB. This underscores the intricate and heterogeneous nature of the BrM tumor immune
microenvironment (TIME) and emphasizes the need for a better understanding of its role driving pro- or anti-tumoral responses. My research has linked the genetic makeup of cancer cells to the abundance and function of immune cells in the microenvironment of human BrMs, suggesting an important role for somatic variation in shaping the TIME.
Furthermore, two recent pan-cancer genome-wide association studies connected highly prevalent germline variants in different loci to specific immune traits and immune-related adverse effects upon ICB therapy in humans. However, the contribution of tumor somatic and host germline variation to anti-tumoral immunity remains to be fully understood. My hypothesis is that genetic variation instructs specific immunophenotypes in the microenvironment of BrM tumors, which in turn shape responses to therapy. Therefore, this proposal aims to: (i) evaluate the efficacy of radio- and ICB therapy in preclinical mouse models of breast-, lung- and melanoma-BrM bearing different combinations of germline and somatic variants; (ii) characterize the TIME in the aforementioned models; (iii) analyze the association between germline variation and immune-related adverse effects linked to ICB in BrM; (iv) explore the link between genetic variation, TIME phenotypes and responses to therapy in human BrMs. If successful, this project will pave the way for the development of personalized immunotherapies for BrM patients tailored by their germline mutations and the somatic makeup of their tumors.