Regulation of immune checkpoint blockade efficacy in breast cancer by FIP200: A canonical-autophagy-independent function

Abstract:

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic strategy because of its potential to induce durable therapeutic responses in cancer patients. However, in the case of breast cancer, its application and efficacy has been limited. As such, combinatorial therapeutic strategies that can unlock the potential of ICB in breast cancer are of urgent need. In view of that, autophagy-related proteins that play a role in the autophagic cell recycling process have been implicated in the regulation of inflammatory and anti-tumor immune responses. Accordingly, autophagy-related proteins represent a group of prospective therapeutic targets in conjunction with ICB. In our recent study (Okamoto T et al. (2020), Cancer Res), we developed immune-competent mouse models of breast cancer which were deficient for the autophagic function of FIP200 or had FIP200 completely ablated to test the efficacy of ICB. We showed that although FIP200’s autophagy function was required for progression of PyMT-driven mammary tumors, FIP200’s canonical-autophagy-independent function was responsible for increased T-cell infiltration, IFN-signaling and ICB efficacy. These findings provide genetic proof of principle for a combinatorial therapeutic strategy that involves ablation of FIP200 to improve ICB efficacy in non-responsive breast cancers.