Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a population-based study

Keane, Colm, Vari, Frank, Hertzberg, Mark, Le Cao, Kim-Anh, Green, Michael R., Han, Erica, Seymour, John F., Hicks, Rodney J., Gill, Devinder, Crooks, Pauline, Gould, Clare, Jones, Kimberley, Griffiths, Lyn R., Talaulikar, Dipti, Jain, Sanjiv, Tobin, Josh and Gandhi, Maher K. (2015) Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a population-based study. Lancet Haematology, 2 10: e445-e455. doi:10.1016/S2352-3026(15)00150-7

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Author Keane, Colm
Vari, Frank
Hertzberg, Mark
Le Cao, Kim-Anh
Green, Michael R.
Han, Erica
Seymour, John F.
Hicks, Rodney J.
Gill, Devinder
Crooks, Pauline
Gould, Clare
Jones, Kimberley
Griffiths, Lyn R.
Talaulikar, Dipti
Jain, Sanjiv
Tobin, Josh
Gandhi, Maher K.
Title Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: a population-based study
Journal name Lancet Haematology   Check publisher's open access policy
ISSN 2352-3026
Publication date 2015-10-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/S2352-3026(15)00150-7
Open Access Status Not yet assessed
Volume 2
Issue 10
Start page e445
End page e455
Total pages 11
Place of publication London, United Kingdom
Publisher The Lancet Publishing Group
Language eng
Abstract 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.
Formatted abstract
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.
Keyword Diffuse large B cell lymphoma
Immunotherapy
PD L1
T cell
Monocyte
Biomarker
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 14 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 23 Oct 2015, 19:30:28 EST by Maher Gandhi on behalf of UQ Diamantina Institute