Research conducted in collaboration with Alex Duval’s team (Inserm UMRS 938, Saint-Antoine Hospital Research Center, Paris) allowed us to better assess the impact of the tumor microenvironment on the prognosis of colorectal tumors. This work also may explain why certain immunotherapies are effective in a particular population of patients with colorectal cancer.
The tumors contain both tumor cells and non-tumor cells. The latter form the “tumor microenvironment”. The cells of the microenvironment can have a major effect on the evolution of the cancerous disease. For example, it is well known that a strong lymphocyte infiltration, typical of tumors with microsatellite instability (MSI), is a factor of good prognosis in colorectal tumors. Interestingly, metastatic MSI tumors respond very well to immunotherapies designed to activate the immune response of patients by releasing T-cell activity (called immune checkpoint-based therapies). Based on this observation, we studied the microenvironment of colorectal tumors, aiming to evaluate the quality of the antitumour immune response in an extremely comprehensive manner. Our results have shown that, within metastatic MSI tumors, the antitumour immune response can not develop because of a very strong expression of factors inactivating T lymphocytes, which are nevertheless present in a large quantity. In the end, the method developed makes it possible to obtain prognostic information that is more accurate than the sole analysis of lymphocyte infiltration. In the future, it may also be particularly useful in guiding the use of immunotherapy based on immune checkpoint inhibitors in the treatment of colorectal cancer.
L. Marisa, M. Svrcek, A. Collura, et al., The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors. JNCI, 2017. PMID: 28922790
After the development of a molecular classification of colorectal cancers internationally accepted, the CIT team is developing a diagnostic and predictive tool to improve the care of patients suffering from these cancers. The first results on the validation of this tool will be presented at the International Congress of the American Association of Clinical Oncology (ASCO), which will take place in Chicago from 2 to 6 June 2017. The ASCO meeting is the most important world congress dedicated to clinical oncology.
The CIT team, in collaboration with the team of Pierre Laurent-Puig, a gastroenterologist at the Georges Pompidou European Hospital in Paris (Inserm UMR-S775, Paris), is developing a tool for the clinical use of the molecular classification of colorectal cancers (1, 2). The utility of this tool for the diagnosis and the prediction of the response to treatment is the object of validation studies carried out on large cohorts of patients. A first study was performed on a cohort of more than 1,700 patients, with or without the targeted treatment Cetuximab, the PETACC-8 clinical trial sponsored by the French Federation of Digestive Cancer (FFCD). The first results of this work have been selected for oral presentation at the ASCO 2017 meeting. This presentation will take place on the morning of Tuesday 6 June at the Clinical Science Symposium: Making Sense of Consensus Molecular subtypes. With nearly 30,000 participants, the ASCO meeting is the opportunity of major announcements for the evolution of clinical practices in oncology.
(1) L. Marisa et al., 2013, Plos Medicine
(2) J. Guinney et al., 2015, Nature Medicine
(3) ASCO, American Society of Clinical Oncology, Annual Meeting 2017
Developed through a collaboration between the CIT team and Pr Hervé Fridman’s lab, MCP-counter software allows, given a transcriptome profile, to robustly measure the abundance of 10 microenvironment cellular populations (T cells, T CD8 cells, NK cells, cytotoxic lymphocytes, B lineage, monocytic lineage, myeloid dendritic cells, neutrophils, endothelial cells, fibroblasts). The authors illustrate the interest of using MCP-counter to study the tumoral microenvironement. By analyzing around 20.000 tumor transcriptomes related to 32 cancer types, they show that MCP-counter faithfully reproduces what is described in the literature concerning these various types of microenvironment populations and their prognostic value. They also show that classifying tumors according to the abundance of these 10 populations allows identifying classes with distinct prognosis. This work has been accepted for publication in Genome Biology (Becht et al. Genome Biology 2016). Using MCP-counter, these authors had previously shown (Becht et al. Clin. Cancer Res. 2016) that in colorectal cancer the information obtained on these 10 microenvironment cell populations was of great interest to guide the choice of immunotherapies .
Oligodendroglial tumours are a subtype of brain tumours accounting for about 10% of gliomas. Most of these tumours share a common genomic alteration – a genomic loss of both chromosomal arms 1p and 19q – but their prognosis remains highly heterogeneous. Thanks to a collaborative effort between the CIT team and the French national network POLA, the genetic material from a large cohort of patients could be deeply analysed at the molecular level. This work led to the identification of 3 previously unknown subtypes of oligodendroglial tumours with 1p/19q co-deletion which are characterized by distinct molecular profiles at the transcriptome, mirnome and methylome levels. One of these subtype shows a more aggressive profile associated with a high activation of MYC oncogenic pathway and a worse prognosis. This work has been recently published in the journal Nature Communications.
An international consortium of 7 research teams, including the CIT team, just published in Nature Medicine  a consensus classification of colorectal cancers (CRC) based on gene expression data.
Based on the analysis of more than 4,000 tumor samples, this work lead to a consensus on the existence of 4 molecular subtypes of colorectal cancers, thoroughly characterized at the molecular and clinical level :
- The ‘MSI immune’ type (14% of cases) : hypermutated tumors, with a majority bearing microsatellite instability (MSI) and a prominent immune infiltration,
- The ‘Canonical‘ type (37% of cases) : tumors with chromosomal instability and mutations in the APC and TP53 genes, illustrating the canonical carcinogenesis described by Fearon and Vogelstein in 1990,
- The ‘Metabolic‘ type (13% of cases) : chiefly mutated in the KRAS oncogene and overexpress metabolic pathways,
- The ‘Mesenchymal‘ type (23% of cases), associated to a bad prognosis : highly infiltrated tumors that overexpress genes of the Epithelial-Mesenchymal transition.
It is the first international collaboration that successfully lead to the molecular classification of a cancer. The classification into 4 molecular subgroups can hereon be used as a standard by the scientific community, in particular for the identification of targeted therapy and for the stratification of clinical trials.
 Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., Marisa, L., Roepman, P., Nyamundanda, G., Angelino, P., et al. (2015). The consensus molecular subtypes of colorectal cancer. Nature Medicine advance online publication.