Abstract 4238: A novel immunotherapy approach by inhibiting nanotube-mediated mitochondrial trafficking between cancer cells and T cells

Abstract

Abstract Trafficking of mitochondria from immune cells to cancer cells via physical nanotubes is a new mechanism by which cancer cells undergo immune evasion. This results in depletion of T cell, which can limit the efficacy of classical immune checkpoint inhibitors. Here we introduce a novel pharmacological inhibitor that inhibits nanotube-mediated mitochondria transfer from immune cell to cancer cell. Our preliminary study implicates the exocyst complex in the nanotube assembly. We performed molecular dynamic simulations to identify the potential inhibitors for the exocyst proteins. We have identified a drug candidate, TS-1, which successfully inhibits the mitochondria transfer from immune cell to cancer cell. Currently we are exploring the modification of the structural component to increase the inhibitory potential of the drug. TS-1-loaded liposome significantly inhibited tumor growth in a 4T1 metastatic breast cancer mouse model. We observed considerable increase in intratumoral T cell population with treatment. Furthermore, the use of TS-1 in combination with an anti-PD1 inhibitor resulted in effective tumor reduction in the 4T1 model, which typically responds poorly to anti-PD1 therapy alone. Conclusion: Taken together, the inhibition of nanotube-mediated mitochondrial hijacking from immune cells emerges as an approach for the development of next generation of immunotherapy agents. Citation Format: Tanmoy Saha, Ruparoshni Jaybalan, HaeLin Jang, Shiladitya Sengupta. A novel immunotherapy approach by inhibiting nanotube-mediated mitochondrial trafficking between cancer cells and T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4238.