A balance score between immune stimulatory and suppressive microenvironments identifies mediators of tumour immunity and predicts pan-cancer survival

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 M ediators of I mmune R esponse A gainst C ancer in so L id micro E nvironments (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.