Establishing standardized immune phenotyping of metastatic melanoma by digital pathology

作者：Bettina Sobottka, Marta Nowak, Anja Laura Frei, Martina Haberecker, Samuel Merki, Mitchell P. Levesque, Reinhard Dummer, Holger Moch, Viktor Hendrik Koelzer, Rudolf Aebersold, Melike Ak, Faisal Alquaddoomi, Jonas Albinus, Ilaria Alborelli, Sonali Andani, Per-Olof Attinger, Marina Bacac, Daniel Baumhoer, Beatrice Beck‐Schimmer, Niko Beerenwinkel, Christian Beisel, Lara Bernasconi, Anne Bertolini, Bernd Bodenmiller, Ximena Bonilla, Ruben Casanova, Stéphane Chevrier, Natalia Chicherova, Maya D’Costa, Esther Danenberg, Natalie J. Davidson, Monica-Andreea Drăganmoch, Stefanie Engler, Martin Erkens, Katja Eschbach, Cinzia Esposito, André Fedier, Pedro Ferreira, Joanna Ficek, Bruno S. Frey, Sandra Goetze, Linda Grob, Gabriele Gut, Detlef Günther, Martina Haberecker, Pirmin Haeuptle, Viola A Heinzelmann-Schwarz, Sylvia Herter, René Holtackers, Tamara Huesser, Anja Irmisch, Francis Jacob, Andrea Jacobs, Tim M. Jaeger, Katharina Jahn, Alva Rani James, Philip M. Jermann, André Kahles, Abdullah Kahraman, Werner Kuebler, Jack Kuipers, Christian P. Kunze, Christian Kurzeder, Kjong-Van Lehmann, Sebastian Lugert, Gerd Maass, Markus Gabriel Manz, Philipp Markolin, Julien Mena, Ulrike Menzel, Julian M. Metzler, Nicola Miglino, Emanuela S. Milani, Simone E. Muenst, Riccardo Murri, Charlotte K.Y. Ng, Stefan Nicolet, Patrick G. A. Pedrioli, Lucas Pelkmans, Salvatore Piscuoglio, Michael Prummer, Mathilde Ritter, Christian Rommel, María Lourdes Rosano-González, Gunnar Rätsch, Natascha Santacroce, Jacobo Sarabia del Castillo, Ramona Schlenker, Petra Catalina Schwalie, Severin Schwan, Tobias Schär, Gabriela Senti, Franziska Singer, Sujana Sivapatham, Berend Snijder, Vipin T. Sreedharan, Stefan G. Stark, Daniel Johannes Stekhoven, Alexandre P. A. Theocharides, Tinu M. Thomas, Markus Tolnay, Vinko Toševski, Nora C. Toussaint, Mustafa A. Tuncel, Marina Tusup, Audrey van Drogen, Marcus Vetter, Tatjana Vlajnic, Sandra Schorderet Weber, William P. Weber, Rebekka Wegmann, Michael Weller, Fabian Wendt, Norbert Wey, Andreas N. WICKI, Mattheus H. E. Wildschut, Bernd Wollscheid, Shuqing Yu, Johanna Ziegler, Marc Zimmermann, Martin Zoche, Gregor Zuend · 发表于：Laboratory Investigation · 年份：2021 · DOI：10.1038/s41374-021-00653-y · 被引用次数：46 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Immunotherapy and Immune Responses

CD8+ tumor-infiltrating T cells can be regarded as one of the most relevant predictive biomarkers in immune-oncology. Highly infiltrated tumors, referred to as inflamed (clinically "hot"), show the most favorable response to immune checkpoint inhibitors in contrast to tumors with a scarce immune infiltrate called immune desert or excluded (clinically "cold"). Nevertheless, quantitative and reproducible methods examining their prevalence within tumors are lacking. We therefore established a computational diagnostic algorithm to quantitatively measure spatial densities of tumor-infiltrating CD8+ T cells by digital pathology within the three known tumor compartments as recommended by the International Immuno-Oncology Biomarker Working Group in 116 prospective metastatic melanomas of the Swiss Tumor Profiler cohort. Workflow robustness was confirmed in 33 samples of an independent retrospective validation cohort. The introduction of the intratumoral tumor center compartment proved to be most relevant for establishing an immune diagnosis in metastatic disease, independent of metastatic site. Cut-off values for reproducible classification were defined and successfully assigned densities into the respective immune diagnostic category in the validation cohort with high sensitivity, specificity, and precision. We provide a robust diagnostic algorithm based on intratumoral and stromal CD8+ T-cell densities in the tumor center compartment that translates spatial densities of tumor-infil...