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. 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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Authors | 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 |
Journal | The Lancet. Haematology
(Lancet Haematol)
Vol. 2
Issue 10
Pg. e445-55
(Oct 2015)
ISSN: 2352-3026 [Electronic] England |
PMID | 26686046
(Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antibodies, Monoclonal, Murine-Derived
- B7-H1 Antigen
- Biomarkers
- CD274 protein, human
- PDCD1 protein, human
- Programmed Cell Death 1 Receptor
- R-CHOP protocol
- Rituximab
- Vincristine
- Doxorubicin
- Cyclophosphamide
- Prednisone
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Murine-Derived
(therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Australia
- B7-H1 Antigen
(immunology)
- Biomarkers
(metabolism)
- CD4-CD8 Ratio
- Cyclophosphamide
(therapeutic use)
- Doxorubicin
(therapeutic use)
- Female
- Humans
- Killer Cells, Natural
(immunology)
- Lymphoma, Large B-Cell, Diffuse
(drug therapy, immunology)
- Male
- Middle Aged
- Prednisone
(therapeutic use)
- Prognosis
- Programmed Cell Death 1 Receptor
(immunology)
- Queensland
- Rituximab
- Survival Rate
- T-Lymphocytes
(immunology)
- Treatment Outcome
- Vincristine
(therapeutic use)
- Young Adult
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