A balance score between immune stimulatory and suppressive microenvironments identifies mediators of tumour immunity and predicts pan-cancer survival
British Journal of Cancer, vol. 124, pp. 760–769
Abstract
Abstract Background The balance between immune-stimulatory and immune-suppressive mechanisms in the tumour microenvironment is associated with tumour rejection and can predict the efficacy of immune checkpoint-inhibition therapies. Methods We consider the observed differences between the transcriptional programmes associated with cancer types where the levels of immune infiltration predict a favourable prognosis versus those in which the immune infiltration predicts an unfavourable prognosis and defined a score named Mediators of Immune Response Against Cancer in soLid microEnvironments (MIRACLE). MIRACLE deconvolves T cell infiltration, from inhibitory mechanisms, such as TGFβ, EMT and PI3Kγ signatures. Results Our score outperforms current state-of-the-art immune signatures as a predictive marker of survival in TCGA (n = 9305, HR: 0.043, p value: 6.7 × 10−36). In a validation cohort (n = 7623), MIRACLE predicts better survival compared to other immune metrics (HR: 0.1985, p value: 2.73 × 10−38). MIRACLE also predicts response to checkpoint-inhibitor therapies (n = 333). The tumour-intrinsic factors inversely associated with the reported score such as EGFR, PRKAR1A and MAP3K1 are frequently associated with immune-suppressive phenotypes. Conclusions The association of cancer outcome with the level of infiltrating immune cells is mediated by the balance of activatory and suppressive factors. MIRACLE accounts for this balance and predicts favourable cancer outcomes.
Authors 11
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Affiliation as printed
Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA
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Affiliation as printed
Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA
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Affiliation as printed
Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA
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Leiden University Medical Center · Sidra Medical and Research Center
Affiliation as printed
Cancer Research Department, Sidra Medicine, Doha, Qatar
Department of Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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Sidra Medical and Research Center
Affiliation as printed
Cancer Research Department, Sidra Medicine, Doha, Qatar
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Refuge Biotechnologies (United States)
Affiliation as printed
Refuge Biotechnologies, Menlo Park, CA, USA
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Affiliation as printed
Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA
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Affiliation as printed
Genomics Research Center (GRC), AbbVie, Lake County, IL, USA
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Davide Bedognetti corresponding
Sidra Medical and Research Center · University of Genoa
Affiliation as printed
Cancer Research Department, Sidra Medicine, Doha, Qatar. dbedognetti@sidra.org
Dipartimento di Medicina Interna e Specialità Mediche, Università degli Studi di Genova, Genova, Italy. dbedognetti@sidra.org
Cancer Research Department, Sidra Medicine, Doha, Qatar
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Josue A. Samayoa corresponding
Affiliation as printed
Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA. josue.samayoa@abbvie.com
Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA
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Michele Ceccarelli corresponding
Biogem · University of Naples Federico II
Affiliation as printed
Department of Electrical Engineering and Information Technology, University of Naples "Federico II", Naples, Italy. michele.ceccarelli@unina.it
Istituto di Ricerche Genetiche "G. Salvatore", Biogem s.c.ar.l, 83031, Ariano Irpino, Italy. michele.ceccarelli@unina.it
Department of Electrical Engineering and Information Technology, University of Naples "Federico II", Naples, Italy
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