1. Academic Validation
  2. FIP200 Suppresses Immune Checkpoint Therapy Responses in Breast Cancers by Limiting AZI2/TBK1/IRF Signaling Independent of Its Canonical Autophagy Function

FIP200 Suppresses Immune Checkpoint Therapy Responses in Breast Cancers by Limiting AZI2/TBK1/IRF Signaling Independent of Its Canonical Autophagy Function

  • Cancer Res. 2020 Sep 1;80(17):3580-3592. doi: 10.1158/0008-5472.CAN-20-0519.
Takako Okamoto  # 1 Syn Kok Yeo  # 1 Mingang Hao 1 Mary Rose Copley 1 Michael A Haas 1 Song Chen 2 Jun-Lin Guan 3
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
  • 2 Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou, China. [email protected] [email protected].
  • 3 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio. [email protected] [email protected].
  • # Contributed equally.
Abstract

Immune checkpoint inhibitors (ICI) have the potential to induce durable therapeutic responses, yet response rates in breast Cancer are modest and limited to particular subtypes. To expand the applicability of ICI, we examined the role of an essential Autophagy gene, FIP200, which has been shown to be important for tumor progression in mammary tumors. Specific disruption of the Autophagy function of FIP200 or complete ablation of FIP200 in genetic mouse models revealed that FIP200 Autophagy function was required for progression of PyMT-driven mammary tumors. However, a noncanonical Autophagy function of FIP200 was responsible for limiting T-cell recruitment and activation of the TBK1-IFN signaling axis. FIP200 also interacted with the TBK1 adaptor protein, AZI2, which was crucial for activation of TBK1 following FIP200 ablation. Accordingly, disrupting the noncanonical Autophagy function of FIP200 in combination with ICI therapy led to superior, durable responses in immune-competent models of breast Cancer. Collectively, these insights could guide future development of therapeutic agents against FIP200 for combinatorial ICI therapies in nonresponsive breast cancers. SIGNIFICANCE: These findings show that deletion of FIP200 enhances immune checkpoint inhibitor efficacy in nonresponsive breast Cancer.

Figures
Products