The immune contexture of primary and metastatic human tumours Nicolas A Giraldo 1,2,3,5 , Etienne Becht 1,2,3,5 , Romain Remark 1,2,3 , Diane Damotte 1,2,3,4 , Catherine Saute` s-Fridman 1,2,3 and Wolf H Fridman 1,2,3 A tumour grows in a complex microenvironment composed of stromal cells, lymphoid and myeloid cells, vascular and lymphatic vessels, and the resultant cytokine and chemokine milieu. In most primary tumours, a strong Th1/cytotoxic T cells infiltration correlates with a longer survival. This beneficial effect can be hampered by the presence of M2 polarized macrophages and high VEGF production. Recent studies revealed that the pattern of the tumour microenvironment remains a major prognostic factor even in the metastatic lesions, while been reproducible between the primary and metastatic tumour. Nevertheless the prognostic impact of the Th1/cytotoxic T cell infiltrate could be different according to the origin of the primary tumour. This model highlights a novel tumour cell-dependent immune contexture that predicts patient’s clinical outcome and has implications in the use of immunotherapies. Addresses 1 INSERM UMRS872, Cordeliers Research Center, Immune Microenvironment and Tumours Laboratory, Paris, France 2 Universite´ Paris Descartes, Paris, France 3 Universite´ Pierre et Marie Curie, Paris, France 4 Department of Pathology, Hoˆ pital Cochin, Paris, France Corresponding author: Fridman, Wolf H (herve.fridman@crc.jussieu.fr) 5 These authors contributed equally to this work. Current Opinion in Immunology 2014, 27:8–15 This review comes from a themed issue on Tumour immunology Edited by Philip K Darcy and David S Ritchie 0952-7915/$ – see front matter, XXXXhttp://dx.doi.org/10.1016/ j.coi.2014.01.001 Introduction The complex network of epithelial and endothelial cells, vascular and lymphatic vessels, as well as myeloid and lymphoid elements present within tumours has been named the tumour microenvironment. More than being just a passive niche where tumour develops, this complex ecosystem impacts tumour evolution and influences clinical outcome [1,2  ]. Cancer natural history follows a complex multistep process [3] in which an organ- specific precancerous lesion, often undetected, becomes a primary tumour that invades the surrounding tissue, while malignant cells penetrate the blood and lymphatic vessels or migrate along sympathetic nerves to form distant metastases [4]. During these different steps the malignant cells interact with their microenvironment, in the primary tumour site, the draining lymph nodes and in the distant organs where they metastasize [4]. The cur- rent best available tool to decipher the role of the diverse elements of the tumour microenvironment in humans is the characterization of the different cellular populations, their location and densities, their functional orientation, their chemokine production and their correlation with patient’s clinical outcome [2  ,5–7,8  ]. The study of large cohorts of human cancers gene expression arrays strength- ens these analyses [9–12]. Furthermore, novel data from immunotherapy trials allow researchers to correlate a particular modulation of the immune contexture with the clinical responses to treatment [13  ]. Indeed the density and the composition of the immune microenvironment are heterogeneous among patients and tumours. It is now well established that in general the tumour infiltration with M2-phenotype macrophages and myeloid derived suppressor cells (MDSC) promotes tumour progression [14  ,15] whereas infiltration of mem- ory cytotoxic and Th1 T lymphocytes are often associated with good clinical outcome [2  ,5,16,17] and good response to immunotherapy [18–20]. The clinical impact of other lymphoid and myeloid cell populations is less consistent and seems dependent on the tumour type and stage [2  ]. Finally, although the vast majority of analyses focus on primary tumours, recent reports shed light on the dialogue between malignant cells and their microenvir- onment at distant metastatic sites [21  ,22  ], allowing to potentially re-visit the paradigm describing the inter- actions between tumours and their microenvironment at the different steps of local invasion and metastasis. The present review analyses recent data from human primary and metastatic tumours in order to propose an integrated view of the ‘in situ’ dialogue between malig- nant cells and the immune and inflammatory microenvir- onment, and its effect on patient’s clinical outcome. Inflammation and immunity: foes and friends The link between inflammation and tumour develop- ment has been extensively recognized [1]. At precancer- ous stages, the presence of chronic inflammation in an organ helps promoting cancer outbreak and growth. The inflammatory context may be the result of viral infections such as HPV in cervical [23] and head and neck carcinoma Available online at www.sciencedirect.com ScienceDirect Current Opinion in Immunology 2014, 27:8–15 www.sciencedirect.com