A variety of species of bacteria are known to colonize human tumours1–11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12–14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.
Bibliographical noteFunding Information:
Acknowledgements We thank the UT MDACC clinical TIL laboratory for processing the tumour specimens; E. Elinav and. J. Suez for providing bacteria cultures; S. Jung and S. Trzebanski for access to their flow cyometer; and S. Cheriyamundath for his help with confocal imaging. This work was supported by the Intramural Research Programs of the National Cancer Institute. Y.S. is supported by the Israel Science Foundation grant no. 696/17, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 770854), MRA (no. 622106), Rising Tide Foundation, Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, Estate of Alice Schwarz-Gardos, Estate of John Hunter, Knell Family, Peter and Patricia Gruber Award and the Hamburger Family. J.A.W is supported by generous philanthropic contributions to the University of Texas MD Anderson Moon Shots Program for support of tumor-line generation, from the Estate of Mady Dukler, the Joel and Mady Dukler Fund for Cancer Research, the Estate of Judith Safirstein, the Estate of Elaine S. Scheye, the Estate of David Levinson, the Hadar Impact Fund, the Fannie Sherr Fund, the Erica Drake Fund, the Estate of Bernard Berkowitz, the Bernard and Audrey Jaffe Foundation and the Jacques Asseoff Trust. K.V. and T.D.L. are supported by the Wellcome Sanger core funding (WT098051). The CLEM studies were conducted at the Irving and Cherna Moskowitz Center for Nano and Bio-Nano Imaging at the Weizmann Institute of Science. J.R.G.-P. is funded by (and whole-genome sequencing was paid for using) NIH NIAID K01AI143881. Whole-genome sequencing of bacteria isolates was performed by the MD Anderson Advanced Technology Genomics Core grant, funded by the CCSG NIH NCI grant CA016672. A.A. is supported by the Israel Science Foundation grant no. 1435/16. D.J.A., K.V. and T.D.L. are supported by the Wellcome Sanger core funding (WT098051).
© 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.