Authors:
Colm Keane, MRCPI, Frank Vari, PhD, Prof Mark Hertzberg, FRACP, Kim-Anh Lê Cao, PhD, Michael R Green, PhD, Erica Han, MB, Prof John F Seymour, FRACP, Prof Rodney J Hicks, FRACP, Devinder Gill, FRCP, Pauline Crooks, BSc, Clare Gould, MBBS, Kimberley Jones, PhD, Prof Lyn R Griffiths, PhD, Dipti Talaulikar, FRACP, Sanjiv Jain, FRCPA, Josh Tobin, MBBS, & Prof Maher K Gandhi, FRACP
Summary:
Background - Risk-stratification of diffuse large B-cell lymphoma (DLBCL) requires identification of patients with disease that is not cured, despite initial treatment with R-CHOP. The prognostic importance of the revised International Prognostic Index (R-IPI) and cell of origin of the malignant B cell are established in DLBCL. We aimed to develop a novel, easily applicable, tissue-based prognostic biomarker based on quantification of the tumour microenvironment that is independent of and additive to the R-IPI and cell of origin.
Methods - We performed digital hybridisation on the NanoString platform to assess the relation between immune effector and inhibitory (checkpoint) genes in 252 formalin-fixed, paraffin-embedded DLBCL tissue specimens obtained from patients treated with R-CHOP. We used a tree-based survival model to quantify net antitumoral immunity (using ratios of immune effector to checkpoint genes) and to generate a cutoff as an outcome predictor in 158 of the 252 patients. We validated this model in tissue (n=233) and blood (n=140) samples from two independent cohorts treated with R-CHOP.
Findings - T-cell and NK-cell immune effector molecule expression correlated with tumour-associated macrophage and PD-1/PD-L1 axis markers, consistent with malignant B cells triggering a dynamic checkpoint response to adapt to and evade immune surveillance. The ratio of CD4*CD8 to (CD163:CD68[M2])*PD-L1 was better able to stratify overall survival than was any one immune marker or combination, distinguishing groups with disparate 4-year overall survival. 94 (59%) of 158 patients had a score above the cutoff and 4-year overall survival of 92•1% (95% CI 82•9–96•7), and the remaining 64 (41%) patients had a score below the cutoff and 4-year overall survival of 47•0% (32•8–60•5; hazard ratio [HR] 8•3, 95% CI 4•3–17•3; p<0•0001). The CD4*CD8:M2*PD-L1 immune ratio was independent of and added to the R-IPI and cell of origin. Tissue findings in the independent tissue cohort accorded with those in our initial tissue cohort. 139 (60%) of 233 patients had a score above the cutoff and 4-year overall survival of 75•6% (95% CI 64•6–83•6), with the remaining 94 (40%) patients having a score below the cutoff (63•5% [52•5–72•7]; HR 1•9, 95% CI 1•1–3•3; p=0•0067).
Interpretation - Ratios of immune effectors to checkpoints augment the cell of origin and R-IPI in DLBCL and are applicable to paraffin-embedded biopsy specimens. These findings might have potential implications for selection of patients for checkpoint blockade within clinical trials.
Source:
The Lancet Haematology; Vol. 2, No. 10, e445-e455 (10/2015)