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, Eui-Ryoung; Seymour, John F.; Hicks, Rodney J.; Gill, Devinder; Crooks, Pauline; Gould, Clare; Jones, Kimberley; Griffiths, Lyn R.; Talaulikar, Dipti; Jain, Sanjiv; Tobin, Joshua W.D.; Gandhi, Maher K.

doi:10.1016/s2352-3026(15)00150-7

Cited by 85 publications

(101 citation statements)

References 40 publications

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“…PD-L1 overexpression has also been described in cancer subtypes beyond those that have been so far considered for immune check point inhibitors [4,10,[24][25][26], potentially opening this type of therapy to a larger and more diverse populations of cancer patients. However, predictive value of immunohistochemical biomarkers (thresholds, cellular distribution, methods of analysis) for the PD-1/PD-L1 axis inhibition need still be refined.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 status in refractory lymphomas

et al. 2016

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Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana). Thirteen PD-L1+ cases were further analyzed for gene copy number variations (CNV) by NGS and for PD-L1/JAK2/PD-L2 co-amplification using fluorescent in-situ hybridization assay (FISH). PD-L1 positivity (!5% positive cancer cells, IHC) was present in 32/77 (42%) and 33/71 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance between the two anti-PD-L1 clones was high with only three (4%) discrepant cases. The strongest and consistent (10/11 cases) expression was observed in cHL and primary mediastinal B-cell lymphomas (3/3). Diffuse large B-cell lymphomas (DLBCL) were frequently positive (13/26) irrespective of subtype. Follicular (1/8), peripheral T-cell (3/11) and mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/CLL and marginal zone lymphomas were consistently negative (3/3). Co-amplification/CNVs of PD-L1/ JAK2/PD-L2 were observed in 3 cases of DLBCL and cHL, respectively. Of note, all three cHL-amplified cases were positive by FISH, but not by NGS. Since only a fraction of the IHC positive lymphoma cases were positive by FISH and NGS assays, other mechanisms are involved in PD-L1 upregulation, especially in DLBCL. FISH assay may be more suitable than NGS assay for determination of PD-L1 alterations in cHL.

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Section: Discussionmentioning

confidence: 99%

PD-L1 status in refractory lymphomas

et al. 2016

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“…Increased T-cell infiltration within the tumor biopsy is associated with improved outcome in CHOP-and R-CHOP-treated patients with DLBCL (2)(3)(4). The association between increased T-cell infiltration and improved survival is also seen in patients with solid tumors (5).…”

Section: Introductionmentioning

confidence: 89%

“…Genes were quantified using the nCounter platform (nanoString Technologies), and the cell of origin (COO) was calculated as previously outlined (2). Flow cytometry was performed as published (3).…”

Section: Translational Relevancementioning

confidence: 99%

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

Keane

Gould

Jones

et al. 2017

Clinical Cancer Research

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Purpose: To investigate the relationship between the intratumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design: We performed high-throughput unbiased TCRb 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 ¼ 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 ¼ 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV þ 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 elevated PD-1, PD-L1, and PD-L2 immune 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.

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“…39 The ratio of CD4*CD8 to (CD163:CD68 [M2])*PD-L1 in histopathological samples of DLBCL patients treated with R-CHOP also indicated differences in OS. 40 Interestingly, soluble plasma PD-L1 (sPD-L1), measured prior to treatment in newly diagnosed DLBCL patients, has also been found to correlate with poorer 3-year OS in multivariate analysis. 41 Of note, serum-levels of sPD-L1 decreased significantly in patients achieving a CR and were attributed to an immunological effect of treatment, suggesting that sPD-L1 levels mirror the host anti-immune response, rather than the specific presence of malignant cells.…”

Section: Large B-cell Lymphomamentioning

confidence: 99%