Tumors grow within a complex microenvironment composed of immune cells, fibroblasts, endothelial cells, and other non-malignant cells. The study of the composition of tumor microenvironments has led to classifications with prognostic and theranostic values, as well as to treatments modulating its composition and its functional orientation. Concurrently, molecular classifications of tumors have proposed taxonomies that define groups of patients with different prognosis and which predict responses to treatments. The density, location, and functional orientation of tumor-infiltrating lymphocytes form the immune contexture, the composition of which is positively correlated in most cases with patient survival. Colorectal cancer represents a paradigm for tumor immunology, as it is the human cancer in which it was exemplified that an adaptive immune response can control tumor growth and metastasis. A high infiltration of Th1/cytotoxic T cells is associated with longer disease or progression free and/or overall survival both in primary and metastatic sites. There are, howewer, exceptions to this rule, such as renal cell carcinoma where high CD8 T cell infiltration correlates with shorter survival. High infiltration by myeloid cells and fibroblats is generally associated with poor prognosis in cancer. We developed and validated a method, called MCP-Counter, which simultaneously quantifies the proportions of 10 different cellular populations in human tissues and applied it to human cancers. The method enabled a microenvironment-based classification of cancers that we correlated with known molecular classifications in colorectal and clear cell renal cell cancers. We confirmed our data by quantifying tumor infiltrating cells by immunohistochemistry. In colorectal cancer, the molecular and immune classifications confirmed that not only microsatellite-instable (MSI) tumors, but also a subgroup of microsatellite-stable (MSS) tumors, are characterized by a favorable immune contexture with high Th1/cytotoxic infiltration. Other subtypes exhibited poor immune infiltation or, in the worst prognostic case, high T cell infiltration in the context of a major inflammatory, angiogenic, and desmoplastic reaction. A group of experts met under the auspices of Fight Colorectal Cancer and the Cancer Research Institute. This group has recently elaborated therapeutic strategies for the different subtypes of colorectal cancer. In clear cell renal cell cancer, we identified a poor prognosis subgroup with high infiltration of CD8 T cells which express checkpoint inhibitors in the presence of PDL-1 and/or PDL-2 expressing tumor cells. In addition, using multiparametric immunophenotyping of tumor-infiltrating T cells, we characterized the lymphocyte populations that correlate with poor prognosis. Our analyses form the basis of a unification of molecular and immune classifications of human cancers, challenge our current views of the relationship between the composition of the tumor microenvironment and patient's prognosis, and suggest immunotherapeutic approaches that could benefit subgroups of patients in different cancers.

Citation Format: Etienne Becht, Nicolas A. Giraldo, Aurélien De Reynies, Pierre Laurent-Puig, Benoit Beuselinck, Jessica Zucman-Rossi, Catherine Sautès-Fridman, Wolf H. Fridman. Tumor microenvironments: Prognostic and theranostic impacts [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA10.