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

Colm Keane, Frank Vari, Mark Hertzberg, Kim Anh Lê Cao, Michael R. Green, Erica Han, John F. Seymour, Rodney J. Hicks, Devinder Gill, Pauline Crooks, Clare Gould, Kimberley Jones, Lyn R. Griffiths, Dipti Talaulikar, Sanjiv Jain, Josh Tobin, Maher K. Gandhi

Research output: Contribution to journalArticle

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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 cutoffas 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 cutoffand 4-year overall survival of 92·1% (95% CI 82·9-96·7), and the remaining 64 (41%) patients had a score below the cutoffand 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 cutoffand 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. Funding: Leukaemia Foundation of Queensland, Kasey-Anne Oklobdzijato Memorial Fund, the Australasian Leukaemia and Lymphoma Group (Malcolm Broomhead Bequest), the Australian Cancer Research Foundation, and the Cancer Council of Queensland.

Original languageEnglish (US)
Pages (from-to)e445-e455
JournalThe Lancet Haematology
Volume2
Issue number10
DOIs
StatePublished - Jan 1 2015

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Lymphoma, Large B-Cell, Diffuse
Biomarkers
T-Lymphocytes
Survival
Population
Queensland
asulacrine
Paraffin
Leukemia
B-Lymphocytes
Neoplasms
CD4-CD8 Ratio
Tumor Microenvironment
Natural Killer Cells
Patient Selection
Formaldehyde
Genes
Immunity
Lymphoma
Macrophages

ASJC Scopus subject areas

  • Hematology

Cite this

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; Cao, Kim Anh Lê; 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.

In: The Lancet Haematology, Vol. 2, No. 10, 01.01.2015, p. e445-e455.

Research output: Contribution to journalArticle

Keane, C, Vari, F, Hertzberg, M, Cao, KAL, Green, MR, Han, E, Seymour, JF, Hicks, RJ, Gill, D, Crooks, P, Gould, C, Jones, K, Griffiths, LR, Talaulikar, D, Jain, S, Tobin, J & Gandhi, MK 2015, 'Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma: A population-based study', The Lancet Haematology, vol. 2, no. 10, pp. e445-e455. https://doi.org/10.1016/S2352-3026(15)00150-7
Keane, Colm ; Vari, Frank ; Hertzberg, Mark ; Cao, Kim Anh Lê ; 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. / Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma : A population-based study. In: The Lancet Haematology. 2015 ; Vol. 2, No. 10. pp. e445-e455.
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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 cutoffas 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 cutoffand 4-year overall survival of 92·1{\%} (95{\%} CI 82·9-96·7), and the remaining 64 (41{\%}) patients had a score below the cutoffand 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 cutoffand 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. Funding: Leukaemia Foundation of Queensland, Kasey-Anne Oklobdzijato Memorial Fund, the Australasian Leukaemia and Lymphoma Group (Malcolm Broomhead Bequest), the Australian Cancer Research Foundation, and the Cancer Council of Queensland.",
author = "Colm Keane and Frank Vari and Mark Hertzberg and Cao, {Kim Anh L{\^e}} and Green, {Michael R.} and Erica Han and Seymour, {John F.} and Hicks, {Rodney J.} and Devinder Gill and Pauline Crooks and Clare Gould and Kimberley Jones and Griffiths, {Lyn R.} and Dipti Talaulikar and Sanjiv Jain and Josh Tobin and Gandhi, {Maher K.}",
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TY - JOUR

T1 - Ratios of T-cell immune effectors and checkpoint molecules as prognostic biomarkers in diffuse large B-cell lymphoma

T2 - A population-based study

AU - Keane, Colm

AU - Vari, Frank

AU - Hertzberg, Mark

AU - Cao, Kim Anh Lê

AU - Green, Michael R.

AU - Han, Erica

AU - Seymour, John F.

AU - Hicks, Rodney J.

AU - Gill, Devinder

AU - Crooks, Pauline

AU - Gould, Clare

AU - Jones, Kimberley

AU - Griffiths, Lyn R.

AU - Talaulikar, Dipti

AU - Jain, Sanjiv

AU - Tobin, Josh

AU - Gandhi, Maher K.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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 cutoffas 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 cutoffand 4-year overall survival of 92·1% (95% CI 82·9-96·7), and the remaining 64 (41%) patients had a score below the cutoffand 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 cutoffand 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. Funding: Leukaemia Foundation of Queensland, Kasey-Anne Oklobdzijato Memorial Fund, the Australasian Leukaemia and Lymphoma Group (Malcolm Broomhead Bequest), the Australian Cancer Research Foundation, and the Cancer Council of Queensland.

AB - 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 cutoffas 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 cutoffand 4-year overall survival of 92·1% (95% CI 82·9-96·7), and the remaining 64 (41%) patients had a score below the cutoffand 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 cutoffand 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. Funding: Leukaemia Foundation of Queensland, Kasey-Anne Oklobdzijato Memorial Fund, the Australasian Leukaemia and Lymphoma Group (Malcolm Broomhead Bequest), the Australian Cancer Research Foundation, and the Cancer Council of Queensland.

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