Valentin Marteau, Niloofar Nemati, Kristina Handler, Deeksha Raju, Alexander Kirchmair, Dietmar Rieder, Erika Kvalem Soto, Georgios Fotakis, G. de Lange, Sandro Carollo, Nina Boeck, Alessia Rossi, Sophia Daum, Alexandra Scheiber, Arno Amann, Andreas Seeber, Elisabeth Gasser, Steffen Ormanns, Michael Günther, Agnieszka Martowicz, Zuzana Loncová, Giorgia Lamberti, Krogsdam Anne, Michela Carlet, Lena Horvath, Marie Theres Eling, Hassan Fazilaty, Tomáš Valenta, Gregor Sturm, Sieghart Sopper, Andreas Pircher, Patrizia Stoitzner, Peter J. Wild, Patrick Welker, Pascal J. May, Paul K. Ziegler, Markus Tschurtschenthaler, Daniel Neureiter, Florian Huemer, Richard Greil, Lukas Weiss, Marieke E. Ijsselsteijn, Noel F. de Miranda, Dominik Wolf, Isabelle C. Arnold, Stefan Salcher, Zlatko Trajanoski
The immune composition of the tumor microenvironment has a major impact on the therapy response in patients with colorectal cancer. Here, we built an atlas with 4.27 million single cells from 1,670 patient samples and complemented it with single-cell profiles from 266 patients, including cells with low mRNA content, spatial transcriptomics from 3.7 million cells, and protein profiles from 0.7 million cells. The analysis of the atlas allows tumor classification into immune desert, B cell enriched, T cell enriched, and myeloid cell enriched immune phenotypes. Within the myeloid compartment, we identify consensus myeloid gene expression programs with four immunomodulatory programs, and uncover a subpopulation of neutrophils with antigen-presenting properties. Moreover, functional experiments using patient-derived organoids show KRAS-dependent pro-tumorigenic polarization of neutrophils. Further, spatial multimodal single-cell profiling reveals niches with IL-1 signaling-based neutrophil-fibroblast interaction. Finally, using an orthotopic mouse model, we show that cancer-derived signals modify neutrophil production in the bone marrow.