The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status. (3rd April 2019)

• Record Type: Journal Article
• Authors: Ott, Eva; Bilonda, Linda; Dansette, Delphine; Deleine, Cécile; Duchalais, Emilie; Podevin, Juliette; Volteau, Christelle; Bennouna, Jaafar; Touchefeu, Yann; Fourquier, Pierre; El Alami Thomas, Wassila; Chetritt, Jérome; Bezieau, Stéphane; Denis, Marc; Toquet, Claire; Mosnier, Jean-François; Jarry, Anne; Bossard, Céline
• Is Part Of: Oncoimmunology. Volume 8:Number 4(2019)
• Publication Date: 2019-04-03
• Subjects: Colorectal cancer -- medullary carcinoma -- Tbet -- microsatellite instability -- IFNγ response -- explant culture -- PD1/PDL1 -- IDO-1 -- PD1 blockade; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2018.1562834
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Purpose : The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology : In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results : The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion : Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment.