HLA-DR Protein Expression Correlates with Non-Neoplastic T-Cell Infiltration and Predicts Survival in Patients with Primary Mediastinal Large B Cell Lymphoma (PMBCL) Treated with CHOP Chemotherapy.
Bibliographic record
Abstract
Abstract 133 Background: PMBCL represents a unique lymphoma type in the WHO classification and shares overlapping histological and gene expression features with both diffuse large B-cell (DLBCL) and classical Hodgkin lymphoma. Similar to DLBCL, PMBCL may show loss of expression of the major histocompatibility class II (MHC II) antigens, which correlates with inferior patient survival (Rimsza, Blood 2006). MHC II proteins are expressed on antigen-presenting cells and are important in eliciting immune responses. In DLBCL, decreased expression of HLA-DR is related to loss of immunosurveillence. Our aim was to validate HLA-DR as an important prognostic biomarker in PMBCL and correlate it with immune response in a cohort of patients treated with multi-agent chemotherapy. Methods: A tissue microarray block was built with duplicate 0.6mm cores of paraffin embedded diagnostic biopsies from 103 patients treated with CHOP/CHOP-like chemotherapy at the BC Cancer Agency (1980-2005). Standard immunohistochemistry was performed with CD20, HLA-DR (IgG2b), CD3, CD4, CD8, CD57, CD68 and cytotoxic markers (TIA1 & Granzyme B). HLA-DR expression was evaluated using a histoscore (intensity of staining and % of positive malignant cells) and correlated with the content (%) of different non-neoplastic infiltrating T-cell subsets and macrophages. Univariate & multivariate analyses were used to characterize overall survival (OS) and progression free survival (PFS). Results: The median follow-up of living patients was 10 years. The IPI predicted OS (p=0.042) but not PFS. Of the 92 cases with interpretable staining, 32 were positive for HLA-DR and 60 negative, with 10-year OS of 86% vs. 61% (p=0.006) and 2-year PFS of 78% vs. 53% (p=0.018), respectively. A Cox multivariate model established both HLA-DR status and IPI as independent predictors of OS (RR=0.3, 95%CI=0.12–0.75, p=0.01; RR=2.9, 95%CI=1.2–6.9, p=0.06, respectively). HLA-DR expression correlated significantly with increased content of all analyzed T cell markers, especially CD3, CD8 and TIA1 (x2, p<0.001), but not with macrophage content (CD68). Of all non-malignant markers, only TIA1+ cell content significantly correlated with survival. Of the 83 cases with interpretable staining, 43 had more than 10% of infiltrating TIA1+ cells and 40 had less, with 10-year OS of 83% vs. 57% (p=0.0014) and 2-year PFS of 76% vs. 50% (p=0.014), respectively. In multivariate analysis, including IPI and HLA-DR and cytotoxic markers, only TIA1 status was an independent predictor of OS (RR=0.3, 95%CI=0.11–0.63, p=0.003). Conclusions: We validated the negative prognostic importance of loss of HLA-DR expression by neoplastic B cells in PMBCL patients treated with multi-agent chemotherapy in a single institution experience. Loss of HLA-DR expression correlated with decreased numbers of infiltrating benign T cell populations, especially CD8+ and TIA1+ cells, where decreased cytotoxic T cell content correlated independently with inferior survival. This study shows loss of immunogenicity and immunosurveillance are key mechanisms in the response to treatment of PMBCL patients and suggests that specific therapies focused on this pathway may benefit patients. Disclosures: Connors: Roche Canada (F Hoffmann-La Roche): Research Funding. Gascoyne:Roche Canada, Genentech, Lilly, Millennium : Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".