Tolga Turan1, Sarah Kongpachith1, Kyle Halliwill1, Jessica Roelands2,3, Wouter Hendrickx2, Francesco M Marincola4, Thomas J Hudson1, Howard J Jacob5, Davide Bedognetti6,7, Josue Samayoa8, Michele Ceccarelli9,10. 1. Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA. 2. Cancer Research Department, Sidra Medicine, Doha, Qatar. 3. Department of Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands. 4. Refuge Biotechnologies, Menlo Park, CA, USA. 5. Genomics Research Center (GRC), AbbVie, Lake County, IL, USA. 6. Cancer Research Department, Sidra Medicine, Doha, Qatar. dbedognetti@sidra.org. 7. Dipartimento di Medicina Interna e Specialità Mediche, Università degli Studi di Genova, Genova, Italy. dbedognetti@sidra.org. 8. Computational Immunology and Oncology (CIAO), AbbVie, Redwood City, CA, USA. josue.samayoa@abbvie.com. 9. Department of Electrical Engineering and Information Technology, University of Naples "Federico II", Naples, Italy. michele.ceccarelli@unina.it. 10. Istituto di Ricerche Genetiche "G. Salvatore", Biogem s.c.ar.l, 83031, Ariano Irpino, Italy. michele.ceccarelli@unina.it.
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.
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.
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