FIP200 Deletion May Enhance Response to Immunotherapy in Breast Cancer

FIP200 deletion was found to enhance the efficacy of immune checkpoint inhibition in patients with nonresponsive breast cancer, according to results presented in Cancer Research.

Findings showed that, through the use of genetic mouse models, the disruption of autophagy function or induction of complete ablation of FIP200, revealed that autophagy function is essential in order for PyMT-driven mammary tumors to progress. Moreover, FIP200's non-canonical autophagy function causes inhibition both in T-cell recruitment and TBK1-IFN signaling axis activation. By using immunotherapy, investigators were able to disrupt FIP200's non-canonical autophagy function and elicit durable responses in immune-competent breast cancer models.

Even after having identified several predictive biomarkers to help foresee patient outcomes on immune checkpoint inhibitors—CD8+ T-cell density, PD-L1 expression, and mutational load of tumors—objective response rates (ORR) are low in patients with TNBC (20%) and a lower ORR within an unselected breast cancer cohort (4.8%). However, additional studies have been launched that are examining the depletion of autophagy-related genes and how they might increase antitumor responses through the stromal or immune compartment.

FIP200, the deletion of which investigators believed to hinder tumor growth, increase CD8+ tumor-infiltrating lymphocytes (TILs) and INF expression, and even regulate tumor immune responses. In the Cancer Research study, investigators sought to demonstrate these benefits through this study, coupled with the highlighting the effects of ablating FIP200 in combination with anti–PD-1 and anti–CTLA-4 therapies to create a superior therapeutic strategy for unresponsive breast cancers.

Investigators tested FIP200's role in autophagy function in an in vivo setting through mammary epithelial-specific FIP200 knock-in mutant mice through the PyMT breast cancer model. cKI-MT mice were found to only express the FIP200-4A mutations from the KI allele of mammary epithelial cells, which specifically abrogate autophagy function within FIP2 by interrupting its interaction with ATG13. Investigators monitored development within these mammary tumors through physical palpation, during which cKI-MT mice were observed as having decreased tumor development compared with the littermate control group. This infers that by blocking FIP200's autophagy function, it is enough to hinder tumor formation in vivo.

Findings also indicated that prevention of autophagy function lead to inhibited growth within the mammary, in addition to hindering lung metastasis. Based on this, the investigators noted that lower incidences of metastases were not due to the reduced tumor growth, but by the act of ablating FIP200's autophagy function. 

Additional tests, which took lysates from multiple primary tumors that were subsequently analyzed through Western blotting, specifically checked for FIP200 expression and autophagy in tumor cells. Through this, investigators found that FIP200 expression had reduced within the cKI-MT population, possibly due to the loss of the floxed allele. Investigators were able to further confirm autophagy blockage following FIP200 deletion after measurements of LC3-II/LC3-I were taken. 

Investigators additionally theorized that by deleting FIP200m, mammary tumorigenesis would be hindered by tumor cell-intrinsic mechanisms, coupled with increased infiltration of CD8+ effector T cells. Additionally, investigators also found a loss in FIP200 autophagy function, though it was not enough to increase CD8+ TILs.

Overall, investigators found that disrupting FIP200's non-canonical autophagy function, combined with immune checkpoint inhibition, yielded a highly durable response in this patient population.

Reference

1. Okamoto T, Yeo SK, Hao M. FIP200 suppresses immune checkpoint therapy responses in breast cancers by limiting AZI2/TBK1/IRF signaling independent of its canonical autophagy function. Cancer Research. 2020;80(17):3580-3592. doi:10.1158/0008-5472.CAN-20-0519