title: The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma.
abstract: Purpose:To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) inde novodiffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design:We performed high-throughput unbiased TCRβ sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline "R-CHOP" therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).Results:The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P< 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%-79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%-88.5%;P= 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%-76.6%) versus 72.6% (95% CI, 58.8%-82.4%,P= 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevatedPD-1, PD-L1, andPD-L2immune checkpoint molecules.Conclusions:Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy.Clin Cancer Res; 23(7); 1820-8. ©2016 AACR.
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia. c.keane@uq.edu.au M.Gandhi@uq.edu.au.|Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Colm
authors.initials: C
authors.lastname: Keane
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.|Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Gould
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Jones
authors.affiliation: Adaptive Biotechnologies, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Hamm
authors.affiliation: Canberra Hospital, Canberra, Australian Capital Territory, Australia.|Australian National University Medical School, Australian Capital Territory, Australia.
authors.forename: Dipti
authors.initials: D
authors.lastname: Talaulikar
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ellis
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Vari
authors.affiliation: Princess Alexandra Hospital, Brisbane, Queensland, Australia.|Pathology Queensland, Brisbane, Queensland, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Birch
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Erica
authors.initials: E
authors.lastname: Han
authors.affiliation: Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Wood
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Le-Cao
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Pauline
authors.initials: P
authors.lastname: Crooks
authors.affiliation: Canberra Hospital, Canberra, Australian Capital Territory, Australia.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Jain
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.|Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Josh
authors.initials: J
authors.lastname: Tobin
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Australia. c.keane@uq.edu.au M.Gandhi@uq.edu.au.|Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Maher K
authors.initials: MK
authors.lastname: Gandhi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D000069283:Rituximab / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000235:genetics*; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone