Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer

• Published in: Immunity (Cambridge, Mass.) Vol. 39; no. 4; pp. 782 - 795
• Main Authors: Bindea, Gabriela, Mlecnik, Bernhard, Tosolini, Marie, Kirilovsky, Amos, Waldner, Maximilian, Obenauf, Anna C., Angell, Helen, Fredriksen, Tessa, Lafontaine, Lucie, Berger, Anne, Bruneval, Patrick, Fridman, Wolf Herman, Becker, Christoph, Pagès, Franck, Speicher, Michael R., Trajanoski, Zlatko, Galon, Jérôme
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2013; Elsevier Limited
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Cancer; Carcinoma - genetics; Carcinoma - immunology; Carcinoma - mortality; Carcinoma - pathology; Cell Movement; Chemokine CXCL13 - genetics; Chemokine CXCL13 - immunology; Colon; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Cytotoxicity; Experiments; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genetic diversity; Genomes; Humans; Immune system; Immunity, Innate; Interleukins - genetics; Interleukins - immunology; Lymphocyte Count; Lymphocytes; Medical prognosis; Medical research; Mice; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - mortality; Neoplasm Recurrence, Local - pathology; Neoplasm Staging; Patients; Protein Stability; Rodents; Survival Analysis; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - pathology; Tumor Microenvironment - immunology; Tumors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.10.003

The complex interactions between tumors and their microenvironment remain to be elucidated. Combining large-scale approaches, we examined the spatio-temporal dynamics of 28 different immune cell types (immunome) infiltrating tumors. We found that the immune infiltrate composition changed at each tumor stage and that particular cells had a major impact on survival. Densities of T follicular helper (Tfh) cells and innate cells increased, whereas most T cell densities decreased along with tumor progression. The number of B cells, which are key players in the core immune network and are associated with prolonged survival, increased at a late stage and showed a dual effect on recurrence and tumor progression. The immune control relevance was demonstrated in three endoscopic orthotopic colon-cancer mouse models. Genomic instability of the chemokine CXCL13 was a mechanism associated with Tfh and B cell infiltration. CXCL13 and IL21 were pivotal factors for the Tfh/B cell axis correlating with survival. This integrative study reveals the immune landscape in human colorectal cancer and the major hallmarks of the microenvironment associated with tumor progression and recurrence. [Display omitted] •Systems biology reveals a network of intratumor T, Tfh and B cells•Tfh and B cell numbers inversely correlate with tumor progression and recurrence•T, Tfh, and B cells control tumor burden in endoscopic CRC mouse models•CXCL13 and its genomic instability is a mechanism for Tfh and B cell infiltration