title: Coordination of intratumoral immune reaction and human colorectal cancer recurrence.
abstract: A role for the immune system in controlling the progression of solid tumors has been established in several mouse models. However, the effect of immune responses and tumor escape on patient prognosis in the context of human cancer is poorly understood. Here, we investigate the cellular and molecular parameters that could describe in situ immune responses in human colorectal cancer according to clinical parameters of metastatic lymph node or distant organ invasion (META- or META+ patients). Primary tumor samples of colorectal carcinoma were analyzed by integrating large-scale phenotypic (flow cytometry, 39 patients) and gene expression (real time reverse transcription-PCR, 103 patients) data sets related to immune and protumoral processes. In META- colorectal cancer primary tumors with high densities of T cells, we observed significant positive correlations between markers of innate immune cells [tumor-associated macrophages, dendritic cells, natural killer (NK) cells, and NKT cells] and markers of early-activated T cells. Significant correlations were also observed between markers of cytotoxic and effector memory T-cell subpopulations. These correlation profiles were absent in tumors with low T-cell infiltrates and were altered in META+ tumors with high T-cell infiltrates. We show that the coexpression of genes mediating cytotoxicity (GNLY) and Th1 adaptive immune responses (IRF1) accurately predicted patient survival independently of the metastatic status. High intratumoral mRNA expression of the proangiogenic mediator vascular endothelial growth factor was associated with significantly reduced survival rates in patients expressing high mRNA levels of GNLY. Investigation of the colorectal cancer primary tumor microenvironment allowed us to uncover the association of favorable outcomes with efficient coordination of the intratumoral immune response.
authors.affiliation: Integrative Cancer Immunology INSERM AVENIR Team 15, INSERM U872, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Camus
authors.forename: Marie
authors.initials: M
authors.lastname: Tosolini
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.forename: Franck
authors.initials: F
authors.lastname: Pagès
authors.forename: Amos
authors.initials: A
authors.lastname: Kirilovsky
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.forename: Anne
authors.initials: A
authors.lastname: Costes
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bindea
authors.forename: Pornpimol
authors.initials: P
authors.lastname: Charoentong
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Trajanoski
authors.forename: Wolf-Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory; D009364:Neoplasm Recurrence, Local / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A