Tumor compartment-specific effects of p70s6k in early triple negative breast cancer: regulation of antitumor immune response and therapeutic implications
Breast cancer is the most common cancer among women with significant death rates and economic impact. In daily routine clinics, breast cancer is usually classified on the basis of three immunohistochemical markers (ER, PR and HER2). Triple-negative breast cancer (TNBC) is a subtype defined by the negativity of all these markers, which shows an adverse clinical course. It is characterized by a considerable gene expression heterogeneity that leads to a lack of availability of targeted therapies. Positive clinical trials relying on various forms of immunotherapy have shifted the paradigm of diverse malignancies from cytotoxics to novel immunomodulator drugs. The results in TNBC, however, are not as positive. In a recent taxonomic effort of the hosting group, TNBC has been re-classified on the basis of the activation status of six protein kinases, which in turn constituted novel targets for this disease. One of them, the 70-kDa ribosomal protein S6 kinase (P70S6K), which was associated with an adverse clinical outcome, showed negative correlation with tumor-infiltrating lymphocytes (TILs) abundance. The fact that P70S6K has been associated with immunosuppressive mechanisms and that there is a positive correlation between the number of TILs and the clinical outcomes in TNBC, suggests that the role of P70S6K may be related to pleiotropic and/or opposing properties of tumor progression. By using a combination of multiparametric flow cytometry, bulk/single-cell gene expression analysis and in vivo experiments in mouse models, this proposal aims to unravel the impact of P70S6K modulation over the already known relevant immune-oncology targets/axes as well as the therapeutic consequences of P70S6K blockade in TNBC. These studies will provide a better understanding of the lymphocyte-related responses modulated by P70S6K, with the potential to find new therapies for patients suffering from TNBC and possibly a broader range of malignances.