Abstract
Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.
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The data that support the findings of this study are available from the corresponding authors upon reasonable request.
References
Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133.e17 (2017).
Sharma, P. & Allison, J. P. Dissecting the mechanisms of immune checkpoint therapy. Nat. Rev. Immunol. 20, 75–76 (2020).
Wolchok, J. Putting the immunologic brakes on cancer. Cell 175, 1452–1454 (2018).
Kulkarni, A. et al. A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer. Nat. Biomed. Eng. 2, 589–599 (2018).
Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).
Tseng, D. et al. Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc. Natl Acad. Sci. USA 110, 11103–11108 (2013).
Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
Önfelt, B., Nedvetzki, S., Yanagi, K. & Davis, D. M. Cutting edge: membrane nanotubes connect immune cells. J. Immunol. 173, 1511–1513 (2004).
Sowinski, S. et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat. Cell Biol. 10, 211–219 (2008).
Gousset, K. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 11, 328–336 (2009).
Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015).
Connor, Y. et al. Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype. Nat. Commun. 6, 8671 (2015).
Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H.-H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).
Ahmad, T. et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 33, 994–1010 (2014).
Wang, X. & Gerdes, H. H. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ. 22, 1181–1191 (2015).
Lu, J. et al. Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells. Oncotarget 8, 15539–15552 (2017).
Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).
Kumar, A. et al. Enhanced oxidative phosphorylation in NKT cells is essential for their survival and function. Proc. Natl Acad. Sci. USA 116, 7439–7448 (2019).
Vyas, S., Zaganjor, E. & Haigis, M. C. Mitochondria and cancer. Cell 166, 555–566 (2016).
Goldman, A. et al. Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance. Sci. Signal. 12, eaas8779 (2019).
Clutton, G., Mollan, K., Hudgens, M. & Goonetilleke, N. A reproducible, objective method using MitoTracker® fluorescent dyes to assess mitochondrial mass in T cells by flow cytometry. Cytometry 95, 450–456 (2019).
Pham, A. H., McCaffery, J. M. & Chan, D. C. Mouse lines with photo-activatable mitochondria to study mitochondrial dynamics. Genesis 50, 833–843 (2012).
Pelletier, M., Billingham, L. K., Ramaswamy, M. & Siegel, R. M. in Methods Enzymol, Vol. 542 (eds Galluzzi, L. & Kroemer, G.) 125–149 (Academic Press, 2014).
Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013).
Hase, K. et al. M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nat. Cell Biol. 11, 1427–1432 (2009).
Hashimoto, M. et al. Potential role of the formation of tunneling nanotubes in HIV-1 spread in macrophages. J. Immunol. 196, 1832–1841 (2016).
Moskalenko, S. et al. The exocyst is a Ral effector complex. Nat. Cell Biol. 4, 66–72 (2002).
Hanna, S. J. et al. The role of Rho-GTPases and actin polymerization during macrophage tunneling nanotube biogenesis. Sci. Rep. 7, 8547 (2017).
Guo, W., Tamanoi, F. & Novick, P. Spatial regulation of the exocyst complex by Rho1 GTPase. Nat. Cell Biol. 3, 353–360 (2001).
Fransson, Å., Ruusala, A. & Aspenström, P. The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem. Biophys. Res. Commun. 344, 500–510 (2006).
Glater, E. E., Megeath, L. J., Stowers, R. S. & Schwarz, T. L. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173, 545–557 (2006).
Arkwright, P. D. et al. Fas stimulation of T lymphocytes promotes rapid intercellular exchange of death signals via membrane nanotubes. Cell Res. 20, 72–88.
Bustelo, X. R., Sauzeau, V. & Berenjeno, I. M. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 29, 356–370 (2007).
Majumder, B. et al. Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. Nat. Commun. 6, 6169 (2015).
Acknowledgements
This work is supported by grants from the National Institute of Health (NIH AR073135_HLJ, CA236702_SS_HLJ, CA214411_SS and CA229772_SS_Co-I), American Lung Association Discovery Grant (LCD-618834_SS) and Department of Defense (DoD PC180355_HLJ and CA201065_HLJ). This work was performed in part at the Center for Nanoscale Systems (CNS), Harvard University, a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), supported by the National Science Foundation. We thank M. Haigis and A. Goldman for help with the PhAM mouse studies. K.K. is a Gilead Sciences Fellow of the Life Sciences Research Foundation.
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T.S. conceived the project, designed and executed the experiments, analysed the data, prepared the figures, and contributed to writing the manuscript. C.D. and R.J. helped in designing and executing the in vitro experiments. S.K. and J.M. helped in designing and executing the in vivo studies and analysed results. A.K. performed the genotyping experiment, analysed results and helped write the manuscript. K.K. helped with the Dendra2 mice and Seahorse studies. P.K.M. and A.B. helped with human tumour explant studies and contributed to the manuscript writing. H.L.J. and S.S. conceptualized and supervised the project, and guided the experimental design, data analysis and manuscript writing.
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S.S. is a co-founder and owns equity in Vyome Therapeutics, Akamara Therapeutics and Invictus Oncology, and receives fees from Famygen and Advamedica. H.L.J. is a founder and owns equity in Curer. A.B. is involved in the following consulting/advisory boards: Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Taiho, Sanofi, Daiichi Pharma/AstraZeneca, Puma, Biothernostics, Phillips, Eli Lilly and Foundation Medicine; A.B. is also contracted via research/grant to the following institutions: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Daiichi Pharma/AstraZeneca and Natera. T.S., C.D., R.J., S.K., A.K., K.K., J.M. and P.K.M. declare no competing interests.
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Saha, T., Dash, C., Jayabalan, R. et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat. Nanotechnol. 17, 98–106 (2022). https://doi.org/10.1038/s41565-021-01000-4
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DOI: https://doi.org/10.1038/s41565-021-01000-4
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