Abstract
Therapeutic blockade of PD-1/PD-L1 shows promising results in Hodgkin’s lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients, but biomarkers predicting such responses are still lacking. To this end, we recently developed a transcriptional scoring of immune escape (IE) in cancer biopsies. Using this method in DLBCL, we identified four stages of IE correlated with overall survival, but whether Hodgkin’s lymphomas (HL) also display this partition was unknown. Thus, we explored the transcriptomic profiles of ~1000 HL and DLBCL using a comparative meta-analysis of their bulk microarrays. Relative to DLBCL, the HL co-clustered at the advanced stage of immune escape, displaying significant enrichment of both IE and T-cell activation genes. Analyses via transcriptome deconvolution and immunohistochemistry showed more CD3+ and CD4+ tumor-infiltrating lymphocytes (TILs) in HL than DLBCL. Both HL and non-GCB DLBCL shared a high abundance of infiltrating CD8+ T-cells, but HL had less CD68+CD163+ macrophages. The same cellular distribution of PD-1 and TIM-3 was observed in HL and DLBCL, though HL had more PD-L1 tumor cells and LAG-3 ME cells. This study illuminates the advanced stage of immune activation and escape in HL, consistent with the response to checkpoint blockade therapies for this type of lymphoma.
Highlights
In order to develop within immunocompetent hosts, it is imperative that tumors evolve several immune escape strategies [1,2,3]
The immune escape strategies in lymphoma may vary between individuals, we have demonstrated that transcriptomic analysis of ~1500 B-NHL transcriptome microarrays consistently identifies significant upregulation of IEGS33 in follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia, and chronic lymphocytic leukemia [25]
The enrichment of 44 genes involved in T-cell activation was scored, and demonstrated that cHL samples exhibited a higher Sample enrichment score (SES) for T-activation than non-GCB and GCB diffuse large B-cell lymphoma (DLBCL)
Summary
In order to develop within immunocompetent hosts, it is imperative that tumors evolve several immune escape strategies [1,2,3]. The impairment of functional anti-tumor responses through the upregulation of the immune checkpoint (ICP) has further expanded the list of immune-escape mechanisms [4,5]. Upon massive overexpression of ICPs by tumor or ME cells, these pathways are subverted in cancer and impair anti-tumor immunity. The most widely studied ICP is currently PD-1/PD-L1, largely due to the impressive clinical efficacy of anti-PD-1 antibodies (e.g., nivolumab) in solid cancers and some lymphomas [6,7,8]. We and others have reported the overexpression of such ICPs in lymphomas by tumor cells and/or ME [5,9,10,11,12,13,14,15]
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