BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes
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ORIGINAL ARTICLE
BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes Lukas Peiffer1,2 · Farnoush Farahpour3 · Ashwin Sriram1,2 · Ivelina Spassova1 · Daniel Hoffmann3 · Linda Kubat1 · Patrizia Stoitzner4 · Thilo Gambichler5 · Antje Sucker6 · Selma Ugurel6 · Dirk Schadendorf6 · Jürgen C. Becker1,2,6 Received: 5 May 2020 / Accepted: 16 November 2020 © The Author(s) 2020
Abstract Background Combined inhibition of BRAF/MEK is an established therapy for melanoma. In addition to its canonical mode of action, effects of BRAF/MEK inhibitors on antitumor immune responses are emerging. Thus, we investigated the effect of these on adaptive immune responses. Patients, methods and results Sequential tumor biopsies obtained before and during BRAF/MEK inhibitor treatment of four (n = 4) melanoma patients were analyzed. Multiplexed immunofluorescence staining of tumor tissue revealed an increased infiltration of CD4+ and C D8+ T cells upon therapy. Determination of the T-cell receptor repertoire usage demonstrated a therapy induced increase in T-cell clonotype richness and diversity. Application of the Grouping of Lymphocyte Interactions by Paratope Hotspots algorithm revealed a pre-existing immune response against melanoma differentiation and cancer testis antigens that expanded preferentially upon therapy. Indeed, most of the T-cell clonotypes found under BRAF/MEK inhibition were already present in lower numbers before therapy. This expansion appears to be facilitated by induction of T-bet and TCF7 in T cells, two transcription factors required for self-renewal and persistence of CD8+ memory T cells. Conclusions Our results suggest that BRAF/MEK inhibition in melanoma patients allows an increased expansion of preexisting melanoma-specific T cells by induction of T-bet and TCF7 in these. Keywords BRAF/MEK inhibition · Tumor microenvironment · T-cell receptor repertoire · TCF7 · MDA · CTA
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02804-4) contains supplementary material, which is available to authorized users. * Jürgen C. Becker [email protected] 1
Deutsches Konsortium Für Translationale Krebsforschung (DKTK), Partner Site Essen, Translational Skin Cancer Research, University of Duisburg-Essen, Universitätsstr. 1, 45141 Essen, Germany
2
Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
3
Bioinformatics and Computational Biophysics, University Duisburg-Essen, Essen, Germany
4
Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
5
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Bochum, Germany
6
Department of Dermatology, University Hospital of Essen, Essen, Germany
Abbreviations AKT Protein kinase B BRAF B-rapidly accelerated fibrosarcoma CDR3 Complementarity determining region 3 CTA Cancer testis antigen ERK Extracellular signal-regulated kinase FFPE Formalin-fixed paraffin-embedded GLIPH G
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