CTLA-4 and PD-1 Pathways Similarities, Differences, and Implications of Their Inhibition (1)
To prevent autoimmunity, numerous immune checkpoint pathways regulate activation of T cells at multiple steps during an immune response, a process called peripheral tolerance. Central to this process are the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) immune checkpoint pathways.
CTLA-4 is a CD28 homolog with much higher binding affinity for B7; however, unlike CD28, binding of CTLA-4 to B7 does not produce a stimulatory signal. Inhibitory signals include direct inhibition at the TCR immune synapse, inhibition of CD28 or its signaling pathway, or increased mobility of T cells leading to decreased ability to interact with APCs. Unlike effector T cells, Tregs constitutively express CTLA-4. In animal models, genetic CTLA-4 deficiency in Tregs impaired their suppressive functions, suggesting to control effector T cells downregulate B7 ligands on APCs, leading to reduced CD28 costimulation.
PD-1 is a member of the B7/CD28 family of costimulatory receptors. It regulates T-cell activation through binding to its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2). PD-1 has a higher binding affinity for PD-L2 than for PD-L1. PD-1 binding inhibits T-cell proliferation, and interferon-γ (IFN-γ), tumor necrosis factor-α, and IL-2 production, and reduces T-cell survival. PD-1 expression is a hallmark of “exhausted” T cells that have experienced high levels of stimulation or reduced CD4+ T-cell help, which occurs during chronic infections and cancer characterized by T-cell dysfunction, resulting in suboptimal control of infections and tumors.
Unlike CTLA-4, which is confined to T cells, PD-1 is more broadly expressed on activated T cells, B cells, and myeloid cells. While CTLA-4 functions during the priming phase of T-cell activation, PD-1 functions during the effector phase, predominantly within peripheral tissues. The B7 ligands for CTLA-4 are expressed by professional APCs, which typically reside in lymph nodes or spleen; however, PD-L1 and PD-L2 are more widely expressed on leukocytes, on nonhematopoietic cells, and in nonlymphoid tissues (PD-L1) and on dendritic cells and monocytes (PD-L2).
CTLA-4 blockade affects the immune priming phase by supporting the activation and proliferation of a higher number of effector T cells, regardless of TCR specificity, and by reducing Treg-mediated suppression of T-cell responses. Effective CTLA-4 blockade may depend on the ability to retain preexisting high-avidity T cells with relevance to the antitumor response. On the other hand, PD-1 blockade works during the effector phase to restore the immune function of T cells in the periphery that have been turned off following extended or high levels of antigen exposure, as in advanced cancer. Tumor PD-L1 expression was the single factor most closely correlated with response to anti-PD-1 blockade, whereas PD-L1 expression on TILs was not associated with response. The differences in timing, location, and nonredundant effects of their actions suggest that blockade of both CTLA-4 and PD-1 or PD-L1 could, in theory, induce proliferation of a higher number of T cells early in an immune response, restore immune responses of previously activated T cells that have become exhausted, and reduce Treg-mediated immunosuppression. In metastatic RCC, preliminary data suggest that the objective response rate is higher with a combination blockade (38% to 43%) than was seen with PD-1 inhibition alone in a different trial (20% to 22%). However, combining CTLA-4 and PD-1 blockade with the aim of increasing efficacy is highly desirable, but combination treatment could prove more toxic. In patients with previously untreated melanoma or recurrent SCLC, the incidence of drug-related grade 3-4 adverse events was 54% to 55% with concurrent blockade compared with 24% to 27% with ipilimumab alone and 15% to 16% with nivolumab alone.
Several markers were identified. They were associated with response, including absolute lymphocyte count, upregulation of the T-cell activation maker-inducible costimulator (ICOS), and the development of a polyfunctional T-cell response to the tumor antigen NY-ESO-1. Especially, patients with PD-L1-expressing tumors or infiltrating immune cells typically have a higher response rate to anti-PD-1 or anti-PD-L1 therapy and may also have improved survival outcomes compared with patients with low or negative PD-L1 expression.