Abstract 4153: Therapeutic targeting autophagy to sensitize cancer immunotherapy in various cancer types
Authors: Qiao Yuanyuan , Choi Jae E. , Vo Josh N. , Tien Jean C. , Wang Lisha , Xiao Lanbo , Simko Stephanie A. , Delekta Andrew D. , Hodge Nathan B. , Desai Parth , Juckette Kristin , Xu Alice , Su Fengyun , Wang Rui , Cao Xuhong , Wang Xiaoju , Wang Xiaoming , Siddiqui Javed , Wang Zhen , Bernard Amélie , Fernandez-Salas Ester , Navone Nora M. , Ding Ke , Eskelinen Eeva-Liisa , Heath Elisabeth I. , Klionsky Daniel J. , Zou Weiping , Chinnaiyan Arul M. 
Published: August 2019

Although cancer immunotherapy has revolutionized cancer treatment, patient response to immunotherapy remains varied. Despite progress, the mechanisms limiting cancer immunotherapy are not yet fully understood. A low number of tumor infiltrating T cells (cold tumor) is one of the limiting factors for cancer immunotherapy. Agents that enhance immunotherapy by shifting cold tumors to hot tumors will greatly benefit cancer immunotherapy. In prostate cancer, the majority of tumors are known to be cold and hence, cancer immunotherapy is not the ideal treatment option. Here, we use a prostate cancer model as an example to demonstrate that modulating the tumor microenvironment through altering autophagy will change the tumor cytokine secretion profile, which in turn attracts immune lymphocytes into the tumor microenvironment. In tandem, we have identified a candidate compound known as ESK981 for such a purpose.

Method A small molecule library was used for screening autophagy activity and cytokine secretion. Various types of human cancer cell lines (prostate, renal, bladder, breast etc.) and multiple syngeneic mouse lines were examined for autophagy activity as well as an in vitro response to interferon stimulation with or without ESK981. A syngeneic mouse prostate cancer was used for the in vivo examination of autophagy as well as the anti-tumor effect by ESK981 monotherapy and/or in combination with anti-PD-1 therapy.

Conclusion We have discovered a robust, novel autophagy-modulating small molecule, named ESK981, for the treatment of various cancer types as a monotherapy. In addition, we have demonstrated that autophagy has an essential role in the anti-tumor effect of immunotherapy, especially for anti-PD-1 in syngeneic prostate cancer model. Therefore, the use of a small molecule such as ESK981 to target autophagy can enhance immunological infiltration induced by cancer immunotherapy, such as immune checkpoint blockade, for non-immunogenic tumors.

Conflict of Interest Statement A.M.C. is a co-founder and serves on the Scientific Advisory Board of Esanik Therapeutics, Inc. which owns to the rights to the clinical development of ESK981. Esanik Therapeutics, Inc. did not fund or approve the conduct of this study.

Funding This project is supported by Prostate Cancer Foundation.

Citation Format: Yuanyuan Qiao, Jae E. Choi, Josh N. Vo, Jean C. Tien, Lisha Wang, Lanbo Xiao, Stephanie A. Simko, Andrew D. Delekta, Nathan B. Hodge, Parth Desai, Kristin Juckette, Alice Xu, Fengyun Su, Rui Wang, Xuhong Cao, Xiaoju Wang, Xiaoming Wang, Javed Siddiqui, Zhen Wang, Amélie Bernard, Ester Fernandez-Salas, Nora M. Navone, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I. Heath, Daniel J. Klionsky, Weiping Zou, Arul M. Chinnaiyan. Therapeutic targeting autophagy to sensitize cancer immunotherapy in various cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4153.