The emerging role of immune checkpoint inhibition in malignant lymphoma

Abstract

To evade elimination by the host immune system, tumor cells commonly exploit physiological immune checkpoint pathways, restraining efficient anti-tumor immune cell function. Growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. This innovative strategy has demonstrated paradigm-shifting clinical activity in various malignancies. Antibodies targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein-4 are also being investigated in lymphoid malignancies with varying levels of activity and a favorable toxicity profile. To date, evaluated only in the setting of relapsed or refractory disease, anti-programmed death 1 antibodies such as nivolumab and pembrolizumab show encouraging response rates particularly in classical Hodgkin lymphoma but also in follicular lymphoma and diffuse-large B-cell lymphoma. As the first immune checkpoint inhibitor in lymphoma, nivolumab was approved for the treatment of relapsed or refractory classical Hodgkin lymphoma by the Food and Drug Administration in May 2016. In this review, we assess the role of the pathways involved and potential rationale of checkpoint inhibition in various lymphoid malignancies. In addition to data from current clinical trials, immune-related side effects, potential limitations and future perspectives including promising combinatory approaches with immune checkpoint inhibition are discussed.

Figure 1.

Inhibition of the immune checkpoints PD-1 and CTLA4 to restore T-cell activation. Antigen-presenting cells (APC) present an antigen (e.g., tumor-associated antigen – TAA) to naïve T cells via interaction of T-cell receptor (TCR) and major histocompatibility 1 (MHC-I) molecule, followed by a co-stimulatory signal by CD28/B7-2 interaction, which leads to T-cell activation. The activation is followed by expression of inhibitory checkpoint molecules such as PD-1 and CTLA-4 on T cells. In an immunosuppressive lymph node microenvironment, APC express corresponding inhibitory ligands, bringing T cells to an inactivated or anergic state (via the CTLA4/B7-1 and/or PD-1/PD-L1/L2 interaction). If co-stimulatory signals overpower the co-inhibitory ones, activated effector T cells are released into the blood stream, where they encounter TAA presented on MHC-I molecules on tumor cells. Co-expression of PD-L1 on tumor cells induces inactivation of tumor-specific effector T cells, disabling adequate T-cell-mediated immune responses. Treatment with immune checkpoint inhibitors (ICI) affects both the priming phase of T-cell activation in lymph nodes and the effector phase in the tumor microenvironment (TME), by blocking the inhibitory checkpoint interaction between activated T cells and APC and/or tumor cells, restoring T-cell activity and leading to T-cell-mediated tumor cell lysis. TCR: T-cell receptor; MHC-I: major histocompatibility complex; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; PD-L2: programmed death-ligand 2; CTLA-4: cytotoxic T-lymphocyte-associated protein 4.

Figure 2.

Potential targets of ICI on lymphocytes and tumor cells. (A) Activated T cells (and natural killer cells to a certain extent) express multiple co-stimulatory and co-inhibitory checkpoint molecules on their surface, all of which are potential targets for immunomodulation by checkpoint agonists (co-stimulatory molecules) or inhibitors (co-inhibitory molecules). (B) Tumor cells evade the host immune system by expressing ligands for co-inhibitory checkpoint molecules on T cells, hence targeting these ligands leads to inactivation of inhibitory pathways and reactivation of tumor-specific T cells. TCR: T-cell receptor; MHC-I: major histocompatibility complex I; TAA: tumor-associated antigen; LAG-3: lymphocyte-activation gene 3; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; PD-1: programmed cell death protein 1; TIM-3: T-cell immunoglobulin and mucin-domain containing-3; TIGIT: T-cell immunoreceptor with Ig and ITIM domains; BTLA: B- and T-lymphocyte attenuator; VISTA: V-domain immunoglobulin suppressor of T-cell activation; KIR: killer cell immunoglobulin-like receptor; ICOS: inducible T-cell co-stimulator; GITR: glucocorticoid-induced TNFR-related protein; HVEM: Herpesvirus entry mediator, PD-L1: programmed death-ligand 1; PD-L2: programmed death-ligand 2.

Figure 3.

Schematic depiction of synergistic effects of ICI and radiotherapy or chemotherapy. Tumors are able to model the tumor microenvironment (TME) as well as the systemic immune system by production of immunosuppressive factors, thus evading the host immune response and assuring their survival. Chemotherapy and ionizing radiation induce immunogenic tumor-cell death by multiple mechanisms. Expression of major histocompatibility complex I (MHC-I) molecules, presenting tumor-associated antigens (TAA), is up-regulated in tumor cells. The release of TAA and danger-associated molecular patterns (DAMP) in TME stimulates dendritic cell (DC) activation. At the same time, DC activation is additionally enhanced by a newly established pro-inflammatory milieu in TME caused by direct effects of chemotherapy and/or radiotherapy. Activated and mature DC provide co-stimulatory signals to naïve T cells in draining lymph nodes, enabling priming of tumor-specific T cells. Addition of immune checkpoint inhibitors synergistically facilitates activation of T cells and T-cell-mediated anti-tumor cytotoxicity, overcoming inhibitory effects caused by tumor-derived immunosuppressive factors.