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The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors

Laetitia Marisa 1 Magali Svrcek 2, 3 Ada Collura 2 Etienne Becht 1 Pascale Cervera 2, 3 Kristell Wanherdrick 2 Olivier Buhard 2 Anastasia Goloudina 2 Vincent Jonchère 2 Janick Selves 4 Gerard Milano 5 Dominique Guenot 6 Romain Cohen 2, 7 Chrystelle Colas 2, 8 Pierre Laurent-Puig Sylviane Olschwang 9, 10, 11 Jérémie H Lefèvre 2, 12 Yann Parc 2, 12 Valérie Boige 13, 14 Côme Lepage 15, 16 Thierry André 2, 7 Jean-François Fléjou 2, 3 Valentin Dérangère 17, 16 François Ghiringhelli 17, 16 Aurélien De Reynies 1 Alex Duval 2, *
Abstract : Background Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided. Results The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004). Conclusions ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01727817
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : vendredi 9 mars 2018 - 15:51:24
Dernière modification le : mercredi 19 août 2020 - 12:08:15

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Laetitia Marisa, Magali Svrcek, Ada Collura, Etienne Becht, Pascale Cervera, et al.. The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors. JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), 2018, 110 (1), pp.68-77. ⟨10.1093/jnci/djx136⟩. ⟨hal-01727817⟩

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