P70-IMMUNEBREAST · Tumor compartment-specific effects of P70S6K in early triple negative breast cancer: regulation of antitumor immune response and therapeutic implications

Tumor compartment-specific effects of P70S6K in early triple negative breast cancer: regulation of antitumor immune response and therapeutic implications

Breast cancer is currently the most frequently occurring cancer worldwide and it shows significant death rates and economic impact. Its incidence is progressively increasing every year. Breast cancer comprises a heterogeneous group of tumors that shows a very diverse biological and clinical behaviour. Triple negative breast cancer (TNBC) is an aggressive subtype which accounts for up to 15% of the new breast cancer cases. It is characterized by the lack of expression of the three classical markers associated to breast cancer. This absence of clear ´disease-defining´ biomarkers, as well as its molecular heterogeneity, constitutes a major problem for finding the appropriate therapeutic options for TNBC patients. In fact, despite the improvement in outcomes achieved in other breast cancer subtypes, the prognosis of TNBC is still dismal: up to 40-50% of the new patients diagnosed with early TNBC will experience distant relapse and death due to their disease. Recently, thanks to a 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 constitute novel targets for this disease. Notably, it was found that the functional status of those kinases informs about the risk of relapse of early TNBC patients. One of those kinases is the 70-kDa ribosomal protein S6 kinase (P70S6K), which was associated with an adverse clinical outcome. Likewise, other studies have also shown that increased levels of activation of P70S6K in breast cancer patients correlate with worse prognosis, reduced disease-free survival and increased metastasis. Preliminary data from the host group suggest that mechanisms of immunosuppression or immune-exclusion are triggered in tumors with high levels of phopho-P70S6K (p-P70S6K, the active form of the kinase). It raises the possibility that inhibition of the activity of P70S6K may relieve local immunosuppression and improve the outcome of patients. Thus, this project was focused on understanding the role of P70S6K in regulating the lymphocyte compartment on TNBC. Specific objectives to be addressed are: (1) To characterize the immune infiltrate at a single cell level among the different TNBC subtypes defined by the levels of p-P70S6K; and (2) To describe the role of P70S6K shaping the immune responses in TNBC and the potential therapeutic benefit of the P70S6K blockade.

Data: CORDIS, © European Union