microRNA expression patterns in tumor infiltrating lymphocytes are strongly associated with response to adoptive cell tr
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ORIGINAL ARTICLE
microRNA expression patterns in tumor infiltrating lymphocytes are strongly associated with response to adoptive cell transfer therapy Gilli Galore‑Haskel1 · Eyal Greenberg1 · Inbal Yahav2 · Ettai Markovits1,3 · Rona Ortenberg1 · Ronnie Shapira‑Fromer1 · Orit Itzhaki1 · Jacob Schachter1,4 · Michal J. Besser1,3 · Gal Markel1,3 Received: 25 April 2020 / Accepted: 24 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 m iRHigh 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. Keywords ACT · microRNA · TIL · Melanoma · Biomarker
Introduction Michal J. Besser and Gal Markel have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02782-7) contains supplementary material, which is available to authorized users. * Gal Markel [email protected] 1
Ella Lemelbaum Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan 526260, Israel
2
Graduate School of Business Administration, Tel Aviv University, Tel Aviv, Israel
3
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
4
Sackler School of Medicine and Tel Aviv University, Tel Aviv, Israel
Melanoma is considered as an immunogenic tumor, expressing a variety of tumor associated antigens [1] and highest mutati
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