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

Abstract

Cancer cells escape immune recognition by exploiting the programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) immune checkpoint axis. Immune checkpoint inhibitors that target PD-1/PD-L1 unleash the properties of effector T cells that are licensed to kill cancer cells. Immune checkpoint blockade has dramatically changed the treatment landscape of many cancers. Following the cancer paradigm, preliminary results of clinical trials in lymphoma have demonstrated that immune checkpoint inhibitors induce remarkable responses in specific subtypes, most notably classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, while in other subtypes, the results vary considerably, from promising to disappointing. Lymphomas that respond to immune checkpoint inhibitors tend to exhibit tumor cells that reside in a T-cell-rich immune microenvironment and display constitutive transcriptional upregulation of genes that facilitate innate immune resistance, such as structural variations of the PD-L1 locus, collectively referred to as T-cell-inflamed lymphomas, while those lacking such characteristics are referred to as noninflamed lymphomas. This distinction is not necessarily a sine qua non of response to immune checkpoint inhibitors, but rather a framework to move the field forward with a more rational approach. In this article, we provide insights on our current understanding of the biological mechanisms of immune checkpoint evasion in specific subtypes of B-cell and T-cell non-Hodgkin lymphomas and summarize the clinical experience of using inhibitors that target immune checkpoints in these subtypes. We also discuss the phenomenon of hyperprogression in T-cell lymphomas, related to the use of such inhibitors when T cells themselves are the target cells, and consider future approaches to refine clinical trials with immune checkpoint inhibitors in non-Hodgkin lymphomas.

Dysfunctions of innate and adaptive immune tumor microenvironment in Waldenström macroglobulinemia

“…Although the interaction of programed cell death protein 1 (PD-1, CD279) with its ligands (PD-L1 and PD-L2) is important for maintaining immune tolerance, reduced T cell activity, and could provide an opportunity for tumor cells to evade immune responses. 32,33 In contrary to no change in PD-1 expression, 13 we observed upregulation of PD-1 on several subsets of T cells, B cells and NK cells in WM. Increased PD-L1 expression shows on T cells and monocytes, while low expression of PD-L1 on clonal cells of patients with WM has been detected.…”

“…Similarly, inhibitory molecules, including PD‐L1 and PD‐L2 were upregulated on both mature and immature B cells, whereas PVR (CD155) was preferentially overexpressed only on immature B cells of WM patients. Although the interaction of programed cell death protein 1 (PD‐1, CD279) with its ligands (PD‐L1 and PD‐L2) is important for maintaining immune tolerance, reduced T cell activity, and could provide an opportunity for tumor cells to evade immune responses 32,33 . In contrary to no change in PD‐1 expression, 13 we observed upregulation of PD‐1 on several subsets of T cells, B cells and NK cells in WM.…”

The effects of nature‐inspired amino acid substitutions on structural and biochemical properties of the E. coli L‐asparaginase EcAIII

“…L‐Asparaginases are divided into three structural Classes (da Silva et al, 2022 ; Loch & Jaskolski, 2021 ). L‐Asparaginases from Class 1, thanks to their high substrate affinity (μM), are used in the treatment of lymphoproliferative disorders (Apostolidis et al, 2020 ; Cachumba et al, 2016 ; Maggi et al, 2017 ; Muneer et al, 2020 ; Patel et al, 2022 ); some of them are also used in the food industry (Paul & Tiwary, 2020 ; Xu et al, 2016 ). Class 3 of L‐asparaginases includes Rhizobium etli ‐type enzymes with an extraordinary catalytic center and (mM) substrate affinity (Loch et al, 2021 ; Moreno‐Enriquez et al, 2012 ).…”

A systematic review and meta-analysis of immune checkpoint therapy in relapsed or refractory non-Hodgkin lymphoma; a friend or foe?

“…Although Apostolidis et al. reviewed the rationale and biological principles behind immune checkpoint inhibition in NHLs [22] , few articles reviewed the task, and to the best of our knowledge, no meta-analysis has assessed the effectiveness and safety of ICI therapy in relapsed or refractory NHL patients. The current review aims to summarize the original data obtained from relevant clinical trials, and also to answer some critical questions; how effective are ICIs as monotherapies in relapsed or refractory NHLs?…”