Colm Keane1, Frank Vari2, Mark Hertzberg3, Kim-Anh Lê Cao2, Michael R Green4, Erica Han2, John F Seymour5, Rodney J Hicks5, Devinder Gill6, Pauline Crooks2, Clare Gould6, Kimberley Jones2, Lyn R Griffiths7, Dipti Talaulikar8, Sanjiv Jain9, Josh Tobin10, Maher K Gandhi11. 1. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Brisbane, QLD, Australia; Genomics Research Centre, Griffith University, Southport, QLD, Australia. 2. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia. 3. Department of Haematology, Prince of Wales Hospital, Sydney, NSW, Australia. 4. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA. 5. Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, VIC, Australia. 6. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Brisbane, QLD, Australia. 7. Genomics Research Centre, Griffith University, Southport, QLD, Australia. 8. Canberra Hospital, Canberra, ACT, Australia; Australian National University Medical School, Acton, ACT, Australia. 9. Canberra Hospital, Canberra, ACT, Australia. 10. Australian National University Medical School, Acton, ACT, Australia. 11. University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Brisbane, QLD, Australia. Electronic address: M.Gandhi@uq.edu.au.
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.
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.
Authors: Janice S Ahn; Ali Al-Habib; Jeffrey A Vos; Aliyah R Sohani; Oralia Barboza-Quintana; Juan P Flores; Sijin Wen; Flavia G Rosado Journal: Ann Clin Lab Sci Date: 2020-03 Impact factor: 1.256
Authors: Sara J McKee; Zewen K Tuong; Takumi Kobayashi; Brianna L Doff; Megan Sf Soon; Michael Nissen; Pui Yeng Lam; Colm Keane; Frank Vari; Davide Moi; Roberta Mazzieri; Graham Leggatt; Maher K Gandhi; Stephen R Mattarollo Journal: Oncoimmunology Date: 2017-12-18 Impact factor: 8.110
Authors: Alexandre S Cristino; Jamie Nourse; Rachael A West; Muhammed Bilal Sabdia; Soi C Law; Jay Gunawardana; Frank Vari; Sally Mujaj; Gayathri Thillaiyampalam; Cameron Snell; Madeline Gough; Colm Keane; Maher K Gandhi Journal: Blood Date: 2019-12-19 Impact factor: 22.113
Authors: M K Gandhi; T Hoang; S C Law; S Brosda; K O'Rourke; J W D Tobin; F Vari; V Murigneux; L Fink; J Gunawardana; C Gould; H Oey; K Bednarska; S Delecluse; R U Trappe; L Merida de Long; M B Sabdia; G Bhagat; G Hapgood; E Blyth; L Clancy; J Wight; E Hawkes; L M Rimsza; A Maguire; K Bojarczuk; B Chapuy; C Keane Journal: Blood Date: 2021-03-18 Impact factor: 22.113
Authors: Kyohei Nakamura; Mika Casey; Harald Oey; Frank Vari; John Stagg; Maher K Gandhi; Mark J Smyth Journal: Leukemia Date: 2020-04-08 Impact factor: 11.528
Authors: Cecilia Carpio; Reda Bouabdallah; Loïc Ysebaert; Juan-Manuel Sancho; Gilles Salles; Raul Cordoba; Antonio Pinto; Mecide Gharibo; Drew Rasco; Carlos Panizo; Jose A Lopez-Martin; Armando Santoro; Antonio Salar; Silvia Damian; Alejandro Martin; Gregor Verhoef; Eric Van den Neste; Maria Wang; Suzana Couto; Soraya Carrancio; Andrew Weng; Xuehai Wang; Frank Schmitz; Xin Wei; Kristen Hege; Matthew W B Trotter; Alberto Risueño; Tonia J Buchholz; Patrick R Hagner; Anita K Gandhi; Michael Pourdehnad; Vincent Ribrag Journal: Blood Date: 2020-03-26 Impact factor: 22.113