Immune checkpoint inhibitors and radiotherapy—concept and review of current literature
Abstract
Traditional chemotherapeutic agents non-selectively eliminate cancer cells at the expense of normal tissue; in an attempt to minimize such effects, a new class of targeted agents, immunotherapy, was introduced in the late 1950s with the discovery of interferons and the development of the first cancer vaccine. Ever since, immunotherapy evolved, exploiting different cellular mechanisms including dendritic cell therapy, monoclonal antibodies, and cytokines. Immune checkpoint inhibitors (ICPI) are the most recent subclass of this family and we herein review the basis of exploiting this new subclass of immunotherapy with radiotherapy in the context of studies evaluating their effects on human subjects and focusing on the synergism between the molecular pathways operating in the background. PubMed was searched for studies evaluating the combined use of ICPI and radiotherapy among human subjects. The majority of studies noted an increased response rate in patients receiving combined therapy with no significant increase in toxicity. Outcomes varied among the different ICPI, and treatment with combined anti-PD-1 and anti-CTLA-4 had a higher response rate compared to either modality alone. Synergistic use of ICPI and radiotherapy has the potential to improve survival, however the specifics regarding treatment plan is dependent on a myriad of factors including the genetic and molecular makeup of the tumor as well as the patient.
Keywords: Immune checkpoint inhibitors (ICPI), radiation therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952022/
Immune checkpoint inhibitors and radiotherapy—concept and review of current literature
Re: Immune checkpoint inhibitors and radiotherapy—concept and review of current literature
Background
Immune checkpoint inhibitors (ICPI) mechanism of actions
Immune checkpoints serve as “suppressors” (1) targeting T cells (2) in a tightly regulated system relying on antigen specificity and signal amplification to modify the behavior of the immune system in response to foreign versus self-antigens (3). Antigen presenting cells (APC) process and express antigens on major histocompatibility complexes (MHC) recognized by T cell receptors. The T-cell receptor recognizes and interlocks with specific peptide-MHC combinations triggering a cascade either to kill the cell expressing the peptide (cytotoxic T cells) or to recruit other components of the immune to link adaptive and innate immunity (helper T cells) (4). The overall immune response is amplified culminating in the release of cytokines, recruitment of immune effectors cells, and strengthening subsequent T cell receptor interactions (3). Checkpoints suppress this activation helping healthy cells evade from the immune system. The same mechanism is exploited by cancer cells through expression of inhibitory ligands and receptors that suppress T-cell effector function; thus building cancer cell mediated immune tolerance (3). ICPI helps overcome this tolerance and in particular three molecules part of the ICPI pathway currently under investigation for pharmacological intervention include: CTLA-4, PD-1, and PD-L1 inhibitor (Figure 1).
Immune checkpoint inhibitors (ICPI) mechanism of actions
Immune checkpoints serve as “suppressors” (1) targeting T cells (2) in a tightly regulated system relying on antigen specificity and signal amplification to modify the behavior of the immune system in response to foreign versus self-antigens (3). Antigen presenting cells (APC) process and express antigens on major histocompatibility complexes (MHC) recognized by T cell receptors. The T-cell receptor recognizes and interlocks with specific peptide-MHC combinations triggering a cascade either to kill the cell expressing the peptide (cytotoxic T cells) or to recruit other components of the immune to link adaptive and innate immunity (helper T cells) (4). The overall immune response is amplified culminating in the release of cytokines, recruitment of immune effectors cells, and strengthening subsequent T cell receptor interactions (3). Checkpoints suppress this activation helping healthy cells evade from the immune system. The same mechanism is exploited by cancer cells through expression of inhibitory ligands and receptors that suppress T-cell effector function; thus building cancer cell mediated immune tolerance (3). ICPI helps overcome this tolerance and in particular three molecules part of the ICPI pathway currently under investigation for pharmacological intervention include: CTLA-4, PD-1, and PD-L1 inhibitor (Figure 1).
Debbie
Re: Immune checkpoint inhibitors and radiotherapy—concept and review of current literature
-CTLA-4 inhibitors
-PD-1 inhibitors
Similar to CTLA-4, the PD-1 receptor interacts with two ligands within the B7 family, PD-L1 and PD-L2 (12) through which T cell proliferation is inhibited and expression of pro-inflammatory markers (IFN- γ, TNF-α, and IL-2) is decreased. In T cells whose receptors have recognized their respective antigen on the T cell receptor, simultaneous stimulation of the PD-1 receptor inhibits phosphorylation of intermediates in the TCR pathway inhibiting activation of T cell (12). On a molecular level, activation of PD-1 receptor switches on the tyrosine based motif, recruiting the Src homology 2-containing tyrosine phosphatase (SHP-2) which serves to dephosphorylate and inhibit phosphoinositide 3-kinase (PI3K) activity, decreasing glucose metabolism and IL-2 secretion (15). PD-1 receptor activation on T-regulatory cells increases transformation of CD4 positive T cells to T regulatory cells further enhancing the anti-inflammatory environment (15). This receptor is important in states of chronic inflammation when T cells have been constantly stimulated (16), however, in instances such as tumors and chronic infections, this safety mechanism against auto-immunity can result in inadequate immune support.
The two ligands, PD-L1 and PD-L2, differ in expression and function: PD-L1 has a wider distribution on leukocytes, tumor cells, nonlymphoid tissue, and its expression can be triggered on parenchymal cells via the local presence of cytokines such as IFN-γ and TNF-α (17,18). Increased expression of PD-L1 by healthy tissue in response to these pro-inflammatory markers allows for peripheral immune tolerance. In contrast, PD-L2 has more limited expression on dendritic cells, monocytes, and mast cells (15), and while PD-L1 modulates CD8+ T cell function, PD-L2 modulates CD4+ function (19). Selectively blocking PD-L1 ligand maintains the interaction between PD-1 and PD-L2 providing self-tolerance and minimizing side effects (3) which otherwise would occur if PD-1 receptor blockade occurs disrupting the interaction between PD-1 receptor and both the PD-L1 and PD-L2 ligands. Decreased PD-1 and PD-L1 interaction increases the number of T cells and pro-inflammatory markers at the tumor site creating an environment more suitable for tumor suppression (20). In order for these interactions to function tumor markers such as PD-1 on tumor infiltrating lymphocytes and PD-L1 on tumor cells have to be present, highlighting the importance of biomarkers to predict effective response to ICPI (21,22).
-PD-1 inhibitors
Similar to CTLA-4, the PD-1 receptor interacts with two ligands within the B7 family, PD-L1 and PD-L2 (12) through which T cell proliferation is inhibited and expression of pro-inflammatory markers (IFN- γ, TNF-α, and IL-2) is decreased. In T cells whose receptors have recognized their respective antigen on the T cell receptor, simultaneous stimulation of the PD-1 receptor inhibits phosphorylation of intermediates in the TCR pathway inhibiting activation of T cell (12). On a molecular level, activation of PD-1 receptor switches on the tyrosine based motif, recruiting the Src homology 2-containing tyrosine phosphatase (SHP-2) which serves to dephosphorylate and inhibit phosphoinositide 3-kinase (PI3K) activity, decreasing glucose metabolism and IL-2 secretion (15). PD-1 receptor activation on T-regulatory cells increases transformation of CD4 positive T cells to T regulatory cells further enhancing the anti-inflammatory environment (15). This receptor is important in states of chronic inflammation when T cells have been constantly stimulated (16), however, in instances such as tumors and chronic infections, this safety mechanism against auto-immunity can result in inadequate immune support.
The two ligands, PD-L1 and PD-L2, differ in expression and function: PD-L1 has a wider distribution on leukocytes, tumor cells, nonlymphoid tissue, and its expression can be triggered on parenchymal cells via the local presence of cytokines such as IFN-γ and TNF-α (17,18). Increased expression of PD-L1 by healthy tissue in response to these pro-inflammatory markers allows for peripheral immune tolerance. In contrast, PD-L2 has more limited expression on dendritic cells, monocytes, and mast cells (15), and while PD-L1 modulates CD8+ T cell function, PD-L2 modulates CD4+ function (19). Selectively blocking PD-L1 ligand maintains the interaction between PD-1 and PD-L2 providing self-tolerance and minimizing side effects (3) which otherwise would occur if PD-1 receptor blockade occurs disrupting the interaction between PD-1 receptor and both the PD-L1 and PD-L2 ligands. Decreased PD-1 and PD-L1 interaction increases the number of T cells and pro-inflammatory markers at the tumor site creating an environment more suitable for tumor suppression (20). In order for these interactions to function tumor markers such as PD-1 on tumor infiltrating lymphocytes and PD-L1 on tumor cells have to be present, highlighting the importance of biomarkers to predict effective response to ICPI (21,22).
Debbie