Unveiling new biomarkers and treatments in breast cancer
Breast cancer comprises a heterogeneous group of tumours with diverse biological and clinical behaviour. Triple-negative breast cancer (TNBC) is the most aggressive type and is characterised by the lack of expression of the three classical breast cancer markers: oestrogen, progesterone and HER2 receptors. This absence of clear ‘disease-defining’ biomarkers alongside TNBC molecular heterogeneity, poses major problems in finding the appropriate therapeutic options.
New biomarkers for triple-negative breast cancer
TNBC has recently been linked with activated forms of six protein kinases, suggesting they may serve as novel targets for this disease. The functional status of those kinases tells us a lot about the risk of relapse of TNBC patients. Undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme, the P70-IMMUNEBREAST project focused on the ribosomal protein S6 kinase (P70S6K), which has been associated with an adverse clinical outcome in breast cancer. The working hypothesis was that the active form of P70S6K may be implicated in immunosuppression or immune exclusion in breast cancer. “Our objective was to examine the role of P70S6K in TNBC immune responses. Specifically, we worked to elucidate the role of P70S6K in regulating the lymphocyte compartment in TNBC,” explains the MSCA research fellow Rebeca Jimeno. The team explored the role of P70S6K in tumour immunogenicity and T cell responses in TNBC by blocking P70S6K activity in vitro in different TNBC cell lines. Results suggested that inhibition of P70S6K activity has a negative effect on anti-cancer T cell responses and promotes immune suppression. They also tested the therapeutic effect of P70S6K blockade in different preclinical models of TNBC. Results revealed that inhibition of P70S6K significantly delayed tumour growth and increased survival of animals with tumours exhibiting active P70S6K.
Tumour-infiltrating lymphocytes in TNBC
Tumour-infiltrating lymphocytes (TILs) are immune cells that are found within solid tumours and their microenvironment and correlate with better clinical outcomes in various types of cancer. Although TILs are gaining attention because of their prognostic role in TNBC, challenges regarding their analytical and clinical validity remain. P70-IMMUNEBREAST analysed the presence of TILs in different TNBC patients based on the levels of active P70S6K. Interestingly, they found a lower percentage of TILs in samples exhibiting hyperactivation of the kinase and an overall deregulated phenotype. “While our study offers valuable data enhancing TNBC classification, further functional studies are necessary to gain a comprehensive understanding of the precise mechanisms through which P70S6K regulates T cell responses in TNBC,” highlights Jimeno. With the increasing incidence of TNBC and the poor life expectancy of patients, advancements in this field are crucial for improving current therapeutic approaches. Further characterisation of phenotypic or activation markers of TILs in relation to P70S6K activation holds the potential to unlock new avenues for investigating immune responses in TNBC. Moreover, a combination of clustering based on P70S6K patterns and immune profiling may pave the way towards personalised therapies for TNBC patients in the future. “By leveraging these approaches, we can aspire to improve the prospects and well-being of TNBC patients,” concludes Jimeno.
Keywords
P70-IMMUNEBREAST, triple-negative breast cancer, TNBC, biomarker, P70S6K, tumour-infiltrating lymphocytes, TILs
