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microRNA expression patterns in tumor infiltrating lymphocytes are strongly associated with response to adoptive cell transfer therapy

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Abstract

Adoptive cell transfer (ACT) using autologous tumor infiltrating lymphocytes (TILs) was previously shown to yield clinical response in metastatic melanoma patients as an advanced line. Unfortunately, there is no reliable marker for predicting who will benefit from the treatment. We analyzed TIL samples from the infusion bags used for treatment of 57 metastatic melanoma patients and compared their microRNA profiles. The discovery cohort included six responding patients and seven patients with progressive disease, as defined by RECIST1.1. High throughput analysis with NanoString nCounter demonstrated significantly higher levels of miR-34a-5p and miR-22-3p among TIL from non-responders. These results were validated in TIL infusion bag samples from an independent cohort of 44 patients, using qRT-PCR of the individual microRNAs. Using classification trees, a data-driven predictive model for response was built, based on the level of expression of these microRNAs. Patients that achieved stable disease were classified with responders, setting apart the patients with progressive disease. Moreover, the expression levels of miR-34a-5p in the infused TIL created distinct survival groups, which strongly supports its role as a potential biomarker for TIL-ACT therapy. Indeed, when tested against autologous melanoma cells, miRLow TIL cultures exhibited significantly higher cytotoxic activity than miRHigh TIL cultures, and expressed features of terminally exhausted effectors. Finally, overexpression of miR-34a-5p or miR-22-3p in TIL inhibited their cytotoxic ability in vitro. Overall, we show that a two-microRNA signature correlates with failure of TIL-ACT therapy and survival in melanoma patients.

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Acknowledgements

The authors would like to thank the Aronson Fund and the Lemelbaum family fund for their generous support. G.M is supported by the Melanoma Research Alliance Saban Family Team Sciences Award, Samueli Foundation Grant for Integrative Immuno-Oncology and Israel Science Foundation Grant 15/1925.

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Author notes

  1. Michal J. Besser and Gal Markel have contributed equally to this work.

Authors and Affiliations

  1. Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, 526260, Israel

    Gilli Galore-Haskel, Eyal Greenberg, Ettai Markovits, Rona Ortenberg, Ronnie Shapira-Fromer, Orit Itzhaki, Jacob Schachter, Michal J. Besser & Gal Markel

  2. Graduate School of Business Administration, Tel Aviv University, Tel Aviv, Israel

    Inbal Yahav

  3. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ettai Markovits, Michal J. Besser & Gal Markel

  4. Sackler School of Medicine and Tel Aviv University, Tel Aviv, Israel

    Jacob Schachter

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  1. Gilli Galore-Haskel
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Galore-Haskel, G., Greenberg, E., Yahav, I. et al. microRNA expression patterns in tumor infiltrating lymphocytes are strongly associated with response to adoptive cell transfer therapy. Cancer Immunol Immunother 70, 1541–1555 (2021). https://doi.org/10.1007/s00262-020-02782-7

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