Immunogenomic and ageing determinants of therapy response in brain metastasis

forthcoming

Cancer represents a critical public health issue, with 2.74 million new cases diagnosed in Europe in 2022. Most cancer-related deaths are attributed to metastatic spread and it is estimated that 20-40% of all cancer patients will develop metastases to the brain (BrM), facing a dismal prognosis. Novel immunotherapies have shown promising outcomes in BrM patients, although a substantial proportion remain unresponsive. This reflects the heterogeneous nature of the tumor immune microenvironment (TIME) and emphasizes the need for a better understanding of its role driving pro- or anti-tumoral responses. My postdoctoral research suggested an important role for genetic variation in human BrM cancer cells regulating the composition and function of the TIME. Likewise, ageing has a major impact in the ability of the immune system to fight cancer. However, how these two key factors interact and influence responses to therapy remains unknown. IMMUNAGENOMICS aims to transform personalized care for BrM patients by offering a multidisciplinary view on the dynamic regulation of the TIME by ageing and genetic variation. Specifically, we will: (i) characterize changes in baseline immunity along ageing;(ii) evaluate responses to radio- and immunotherapy in young and aged mouse models of BrM bearing different somatic mutations; (iii) analyze the TIME of BrM tumors from young and aged mice, pre and post-treatment by complementary orthogonal approaches including: flow cytometry, hyperplexed immunofluorescence imaging, scRNA-Seq and spatial transcriptomics; (iv) examine the link between ageing, genetic variation, TIME phenotypes and responses to therapy in collections of banked human BrM samples. Overall, I envision that IMMUNAGENOMICS will help decipher the complex interplay between ageing and genomic variation shaping immune responses against BrM tumors, ultimately opening new perspectives for the development of more effective personalized therapies for this devastating form of cancer