Abstract 1480: A novel mechanism of immunosuppression via nanotube mediated mitochondrial trafficking between cancer cell and immune cell

Abstract Cancer cells deploy multiple mechanisms for immune evasion. Here we report a novel mechanism of cancer cell-induced immune evasion via organelle trafficking between cancer cells and immune cells through physical nanotubes. Using high resolution scanning electron microscopy to analyze a co-culture assay of breast cancer cells and NKT cells revealed that the cancer cells and NKT cells form physical nanotube connections at early time points. Immunofluorescence imaging and quantification using flow cytometry revealed that the cancer cells rapidly hijack mitochondria from immune cells through these nanotubes. The transfer of mitochondria from immune cell to cancer cells imposes a metabolic impairment and results in a reduced population of immune cells. This is not observed in a control coculture using a Boyden chamber, where the two cell types are prevented from forming nanotubes. As the nanotubes are assembled via cytoskeletal rearrangement, we next tested whether the members of Rho-family of GTPases, Cdc42, Ral and Rac are involved in the actin polymerization. Indeed, an inhibitor for Cdc42/Rac1 GTPase inhibitor (ML141) and a geranylgeranyltransferase 1 inhibitor (L-778,123) significantly decreased mitochondrial transfer, and prevented the depletion of NKT cells in co-culture. Furthermore, treating 4T1 tumor-bearing animals with a combination of L-778,123 and a PD1 immune checkpoint inhibitor increased the anti-tumor efficacy compared to PD1 inhibition alone. Conclusion: Our study sheds insights on a novel mechanism of cancer immune suppression via nanotube-mediated intercellular organelle trafficking. The efficacy of GTPase- or geranylgeranyltransferase-inhibitors, in perturbing this process, and the increased efficacy of the combination with PD1 inhibitor, opens up the possibility of developing these as novel immunotherapy agents for cancer. Citation Format: Tanmoy Saha, Chinmayee Dash, Sachin Khiste, Shiladitya Sengupta. A novel mechanism of immunosuppression via nanotube mediated mitochondrial trafficking between cancer cell and immune cell [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 1480.