The clinical development of effective cancer immunotherapies, along with advances in genomic analysis, has led to the identification of tumor environmental features that predict for sensitivity to immune checkpoint blockade therapy (CBT). Early-phase clinical trial results have demonstrated the remarkable effectiveness of CBT in specific lymphoma subtypes, including classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Conversely, CBT has been relatively disappointing in follicular lymphoma and diffuse large B-cell lymphoma. These clinical observations, coupled with important scientific discoveries, have uncovered salient features of the lymphoma microenvironment that correlate with immunotherapy response in patients. For example, classical Hodgkin lymphoma is characterized by an inflammatory environment, genetic alterations that facilitate escape from immune attack, and sensitivity to PD-1 blockade therapy. On the other hand, for lymphomas in which measures of immune surveillance are lacking, including follicular lymphoma and most diffuse large B-cell lymphomas, anti-PD-1 therapy has been less effective. An improved understanding of the immune landscapes of these lymphomas is needed to define subsets that might benefit from CBT. In this article, we describe the immune environments associated with major B-cell lymphomas with an emphasis on the immune escape pathways orchestrated by these diseases. We also discuss how oncogenic alterations in lymphoma cells may affect the cellular composition of the immune environment and ultimately, vulnerability to CBT. Finally, we highlight key areas for future investigation, including the need for the development of biomarkers that predict for sensitivity to CBT in lymphoma patients.

Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non–germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1–altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.

The mechanisms through which immune responses are generated against solid cancers are well-characterized, and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways which regulate immune activation or tolerance are less clear. Growing evidence suggests that, while a number of immune escape pathways are shared between hematological and solid malignancies, there are several unique pathways exploited by leukemia and lymphoma. Below, we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapy approaches.