Abstract
The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor-induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD-1 mediated immune suppression in a range of cancers. However, while PD-1 blockade has been paradigm-shifting in many malignancies, the majority of cancers show high rates of primary resistance to this approach. This has led to a rapid expansion in therapeutic targeting of other immune checkpoint molecules to provide combination immune checkpoint blockade (ICB), with one such promising approach is blockade of Lymphocyte Activation Gene 3 (LAG-3). Clinically, lymphoproliferative disorders show a wide spectrum of responses to ICB. Specific subtypes including classical Hodgkin lymphoma have demonstrated striking efficacy with anti-PD-1 therapy. Conversely, early trials of ICB have been relatively disappointing in common subtypes of Non-Hodgkin lymphoma. In this review, we describe the TME of common lymphoma subtypes with an emphasis on the role of prominent immune checkpoint molecules PD-1 and LAG3. We will also discuss current clinical evidence for ICB in lymphoma and highlight key areas for further investigation where synergistic dual checkpoint blockade of LAG-3 and PD-1 could be used to overcome ICB resistance.
Highlights
Inhibitory checkpoint receptors play a critical role in immune homeostasis
Binding of IFN-γ to its receptor triggers a signaling cascade mediated via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, that results in increased expression of a range of transcription factors, known as the interferon-responsive factors (IRFs) [26]
In lymphoma there are multiple ongoing clinical trials examining the effectiveness of Programmed Death-1 (PD-1) blockade, and regulatory approval has been granted for anti-PD-1 therapy in primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin Lymphoma in the relapsed/refractory (R/R) setting
Summary
Inhibitory checkpoint receptors play a critical role in immune homeostasis. In health, the expression of checkpoint receptors is upregulated following the activation of antigen specific T-cells to temper the pro-inflammatory response. Binding of IFN-γ to its receptor triggers a signaling cascade mediated via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, that results in increased expression of a range of transcription factors, known as the interferon-responsive factors (IRFs) [26]. Of those factors, IRF-1 has been shown to play a central role in the IFN-γ-mediated induction of PD-L1 and to a lesser extent PD-L2 [11,20,27]. In lymphoma there are multiple ongoing clinical trials examining the effectiveness of PD-1 blockade, and regulatory approval has been granted for anti-PD-1 therapy in primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin Lymphoma (cHL) in the relapsed/refractory (R/R) setting
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