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Selected Publications

Breaking the performance ceiling for neoantigen immunogenicity prediction

OBrien H., Salm M., Morton L., Szukszto M., OFarrell F., Boulton C., Becker P. D., Samuels Y., Swanton C., Mansour M. R., Reker Hadrup S. & Quezada S. A. (2023) Nature Cancer. 4, 12, p. 1618-1621

s43018-023-00675-z.pdf

Identification of bacteria-derived HLA-bound peptides in melanoma

Kalaora S., Nagler A., Nejman D., Alon M., Barbolin C., Barnea E., Ketelaars S. L. C., Cheng K., Vervier K., Shental N., Bussi Y., Rotkopf R., Levy R., Benedek G., Trabish S., Dadosh T., Levin-Zaidman S., Geller L. T., Wang K., Greenberg P., Yagel G., Peri A., Fuks G., Bhardwaj N., Reuben A., Hermida L., Johnson S. B., Galloway-Peña J. R., Shropshire W. C., Bernatchez C., Haymaker C., Arora R., Roitman L., Eilam R., Weinberger A., Lotan-Pompan M., Lotem M., Levin Y., Lawley T. D., Adams D. J., Levesque M. P., Besser M. J., Schachter J., Golani O., Segal E., Ruppin E., Kvistborg P., Peterson S. N., Wargo J. A., Straussman R. & Samuels Y. (2021) Nature (London). 592, 7852, p. 138-143

Accepted version

Identification of bacteria-derived HLA-bound.pdf

A variety of species of bacteria are known to colonize human tumours¹¹¹, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment¹²¹⁴. 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.

Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma

Peri A., Greenstein E., Alon M., Pai J. A., Dingjan T., Reich-Zeliger S., Barnea E., Barbolin C., Levy R., Arnedo-Pac C., Kalaora S., Dassa B., Feldmesser E., Shang P., Greenberg P., Levin Y., Benedek G., Levesque M. P., Adams D. J., Lotem M., Wilmott J. S., Scolyer R. A., Jönsson G. B., Admon A., Rosenberg S. A., Cohen C. J., Niv M. Y., Lopez-Bigas N., Satpathy A. T., Friedman N. & Samuels Y. (2021) Journal of Clinical Investigation. 131, 20, e129466.

Combined presentation and immunogenicity analysis.pdf

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote "off-the-shelf" precision immunotherapies, alleviating limitations of personalized treatments.

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Research

Our long-term goal is to create a more comprehensive atlas of the cancer-specific immunopeptidome landscape and provide new targets for immunotherapy, ultimately utilizing this knowledge to pave the way to new personalized immunotherapies based on the cancer-specific antigen landscape and immune state, primarily in melanoma.

Our strategy involves the application of a multi-faceted approach using our melanoma tumor bank, our established rich genetic database, coupled with novel functional genomics and proteomic and peptidomic techniques, as well as computational tools.

Expanding our knowledge of tumor-immune-cell interactions in cancer and the analysis of these interactions could have major clinical relevance, as it may lead to the identification of predictive therapeutic biomarkers and the development of novel therapeutic strategies.

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News

November 20, 2024

Dr. Lea Monteran Receives the Prestigious Koshland Prize and Sir Charles Clore Postdoctoral Fellowship

November 6, 2024

Our Very Own Shira Sagie Receives Mavri Grant for Physician Scientists

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