The immune landscape and response to immune checkpoint blockade therapy in lymphoma

Abstract

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.

Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

“…In a similar manner, stratifying lymphomas into inflamed or noninflamed based on the underlying patterns of tumor immunobiology is a rational approach since it provides the means of selecting patients that may benefit from a more personalized approach, incorporating ICIs in the treatment algorithm of disease entities that are sensitive to PD-1/PD-L1 therapy [ 22 ]. Interestingly, although interferon- γ -mediated upregulation of PD-L1 is a common mechanism of immune adaptive resistance in cancer, upregulation of PD-L1 in lymphomas is frequently driven constitutively by genomic alterations, including structural variation (SVs) in the chromosome region 9p24.1 [ 23 – 28 ], the gene loci where the immunoregulatory genes PD-L1 and PD-L2 reside.…”

Immunotherapy by Immune Checkpoint Inhibitors and Nuclear Medicine Imaging: Current and Future Applications

“…Moreover, in a retrospective multicentric study including 45 patients with Hodgkin lymphoma treated by nivolumab, the classification at the 18 F-FDG PET performed at 2.0 months (interquartile range: 1.7-3.7 months) was identical between Lugano criteria and LYRIC, since all 16 progression events on this examination classified as an indeterminate response per LYRIC were confirmed as progressive diseases on subsequent evaluations [72]. In most other types of lymphoma, including follicular lymphoma and diffuse large B cell lymphoma, ICIs have been rarely used to date, because they are less effective, and therefore, there is a lack of data regarding their therapeutic evaluation [73].…”

Targeting immune checkpoints in hematological malignancies

“…The TME of classical HL consists of rare (0.1–1%) malignant cells called Hodgkin Reed-Sternberg (HRS) cells and an abundant immune cell infiltrate which is markedly distinct from the TME observed in non-Hodgkin’s lymphoma (NHL) [ 69 ]. Thus, the unique immunologically “hot” (or inflamed) TME critically contributes to responsiveness to PD-1 blockade [ 70 ]. To understand the immune landscape, Cader et al recently performed mass cytometry of 7 newly diagnosed classical HL patients [ 71 ].…”

“…The immunologically “cold” TME is created by tumor-intrinsic factors such as high proliferation rate of lymphoma cells and oncogene-driven immune exclusion [ 70 ]. Various factors are reported to be associated with immunologically “cold” TME such as double rearrangements of MYC and BCL2 and/or BCL6 [ 80 ], deletion or mutation of PTEN [ 81 ], and Epstein-Barr virus-related subtypes [ 82 ].…”