Mapping the immune landscape in metastatic melanoma reveals localized cell-cell interactions that predict immunotherapy response

Asier Antoranz, Yannick Van Herck, Maddalena M. Bolognesi, Seodhna Lynch, Arman Rahman, William M. Gallagher, Veerle Boecxstaens, Jean-Christophe Marine, Giorgio Cattoretti, Joost J. van den Oord, Frederik De Smet, Oliver Bechter, Francesca M. Bosisio

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While immune checkpoint-based immunotherapy (ICI) shows promising clinical results in cancer patients, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and non-malignant cells. Although insights into the mechanisms that modulate the pivotal anti-tumoral activity of cytotoxic T-cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types. Here, we used multiplexed immunohistochemistry to spatially characterize the immune landscape of metastatic melanoma from responders and non-responders to ICI. Such high-dimensional pathology maps showed that Tcy gradually evolve towards an exhausted phenotype as they approach and infiltrate the tumor. Moreover, a key cellular interaction network functionally linked Tcy and PD-L1+ macrophages. Mapping the respective spatial distributions of these two cell populations predicted response to anti-PD-1 immunotherapy with high confidence. These results suggest that baseline measurements of the spatial context should be integrated in the design of predictive biomarkers to identify patients likely to benefit from ICI.
Original languageEnglish
Pages (from-to)3275-3290
Number of pages16
JournalCancer Research
Issue number18
Early online date14 Jul 2022
Publication statusPublished - 15 Sep 2022

Bibliographical note

A. Antoranz was partially funded by the KU Leuven funding (C3/19/053), Opening the Future Campaign of the KU Leuven University Fund, and by Kom op tegen Kanker (Stand Up To Cancer), the Flemish cancer society. F.M. Bosisio was funded by KUL INTERNE FONDSEN MIDDEL-Zware infrastructuren EMHD8191-AKUL/19/30 I005920N, FWO Fundamenteel Klinisch Mandaat EMHD8972-FKM/20, Impulsbudget UZ Leuven 2018. W.M. Gallagher, S.M. Lynch, and A. Rahman were funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement #642295 (MEL-PLEX), by the European Union’s FP7 Marie Skłodowska-Curie Industry-Academia Partnership and Pathways research programme under the grant agreement #611107 (SYS-MEL), and by the Science Foundation Ireland Investigator Programme (OPTi-PREDICT; 15/IA/3104) and the Science Foundation Ireland Strategic Partnership Programme (Precision Oncology Ireland; 18/SPP/ 3522). M.M. Bolognesi and G. Cattoretti were funded by the Regione Lombardia POR FESR 2014–2020, Call HUB Ricerca ed Innovazione: ImmunHUB.

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