Methionine supplementation improves the efficacy of breast cancer immunotherapy

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype which is clinically difficult to treat, due the lack of targeted therapies. The low specificity and high relapse rates associated to cytotoxic chemotherapy have encouraged the use of immunotherapy as an alternative treatment option, however, overall response rates to anti-PD-1 immunotherapy are still low. In order to improve the current TNBC immunotherapy efficacy, we thought to use supplementation of methionine - an amino acid with antioxidant properties - to decrease the tumour immunosuppression and increase anti-tumour T cell response. To test our hypothesis, in vivo supplementation of methionine was combined with anti-PD-1 immunotherapy to treat TNBC-bearing mice. In this master thesis, we show that methionine supplementation improves anti-PD-1 treatment efficacy in E0771 TNBC tumour model by delaying the tumour growth. Furthermore, an accumulation of tumour-infiltrating lymphocytes (TILs), such as CD8 and γδ T cells was observed in anti-PD-1 and methionine treated mice. Analysis of tumour-bearing TCRδKO mice revealed a possible role for γδ T cells in inducing CD8 T cell accumulation within the tumour, since CD8 T cell number was no longer increased upon combined treatment in this mouse strain. Moreover, we observed a decreased frequency of TNFα and IFNγ producing CD8 T cells in anti-PD-1 + methionine treated TCRδKO mice, thus suggesting a key role of γδ T cells in potentiating anti-tumour CD8 T cell responses in the presence of PD-1 inhibitor and methionine. Collectively, the work presented in this thesis showed, for the first time, that methionine supplementation in combination with anti-PD-1 antibody can exert a protective role in tumour immunity. Further studies are required to understand the molecular mechanisms behind this positive effect of methionine supplementation, and to evaluate a potential application of this combination in TNBC patients