MSI status plus immunoscore to select metastatic colorectal cancer patients for immunotherapies
Authors: J. Galon, B. Mlecnik, F. Hermitte, F. Marliot, C. Bifulco, A. Lugli, I.D. Nagtegaal, A. Hartmann, M. van den Eynde, M. Roehrl, P. Ohashi, E. Zavadova, T. Torigoe, P. Patel, Y. Wang, Y. Kawakami, F.M. Marincola, P.A. Ascierto, B. Fox, F. Pagès
Journal: Annals of Oncology (2018)

Background: Only a fraction of patients with metastatic disease respond to immune checkpoint inhibitors (ICI). Responders are more likely to be defective in mismatch repair genes (MSI+). MSI+ patients are over-represented in the group of tumors with high densities of CD8 T-cells. Patients with High T-cell infiltration have a higher expression of PD-1 and PDL1, and are more likely to respond to ICI. These observations suggest that the response to ICI is strongly dependent on the presence of an established in situ adaptive immune reaction (Mlecnik Immunity 2016). MSI + colon cancer stage IV patients are eligible to ICI. However this only concerns a minority of patients. Taking into account the evaluation of the in situ immune reaction in the primary tumor together with MSI status could clarify and extend the range of patients eligible to ICI. Methods: Immunoscore is a robust and validated IVD test measuring the host immune reaction (CD3+ and CD8+ cells) at the tumor site. Immunoscore classifies patients' tumors into High, Intermediate or Low. We investigated the Immunoscore (IS) distribution of primary tumors of UICC-TNM stage I-III patients who experienced metachronous metastase(s) from the Immunoscore international validation cohort (Pagès The Lancet 2018). MSI status was assessed with the molecular new Bethesda panel and by IHC. Results: We recorded 1579 UICC-TNM stage I/II/III patients with available MSI status and IS. 318 patients (20%) experienced a relapse. Among those patients, 36 patients (11%) were MSI+ whereas the vast majority of them (89%; 282 patients) were MSS. 43 patients (13%) were IS High, 136 patients (43%) were IS Intermediate and 139 patients (44%) were IS Low. Importantly, 33 patients (12%) were classified IS High in MSS tumors. Combining MSI+ status with IS high to select patients for ICI extends from 11% to 22% the patients eligible to such immunotherapy. Conclusions: The proportion of metastatic colon cancer patients eligible for ICI could be refined and extended by the characterization of their primary tumor immune infiltrate based on the Immunoscore status, as suggested by Le et al (Cancer Immunol Res 2017). Interventional trials are now needed to validate the predictive value of Immunoscore. Legal entity responsible for the study: Society for Immunotherapy of Cancer SITC. Funding: French National Institute of Health and Medical Research, LabEx Immuno-oncology, Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants, Society for Immunotherapy of Cancer. Disclosure: J. Galon: HalioDx Co-founder /SAB; Consult/ Grts: PE, IObiotech, MedImmune, Janssen, BMS, AstraZeneca, Novartis, Definiens, Merck Serono, IObiotech, Nanostring, Illum., Northwest, Actelion, Amgen, Kite Pharma, Roche, GSK, Compugen, Mologen. F. Hermitte: Employee and co-founder: HalioDx. M. Roehrl: Consulting/Advisory roles: Member, Scientific advisory board: Proscia, Baltimore, MD - Member, Scientific advisory board, Trans-Hit, Montreal, QC - Advisor, Gerson Lehrman Group F.M. Marincola: Employee: Abbvie. B. Fox, F. Pagès: Immunoscore Patent (INSERM) co-inventor. All other authors have declared no conflicts of interest.