Checkpoint blockade in cancer immunotherapy

Abstract

The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.

Figure 1

CTLA-4 blockade in cancer immunotherapy. Dendritic cells can sample tumor antigens and present them to T cells. (A) Although activation of dendritic cells may result in upregulation of B7.1/B7.2, the potentially responsive T cells expressing reactive TCR may be inhibited from effector function by inhibitory signaling via CTLA-4 and PD-1. (B) Blockade of CTLA-4 signaling may allow unopposed CD28 costimulation, resulting in recruitment of these T cells as antitumor effectors, either directly or as helpers of CD8-mediated T cells responses. (C) Activated cytotoxic T cells can then affect antitumor responses. (D) CTLA-4 expressing regulatory T cell populations may still be locally active in suppressing antitumor responses. Their activity could also be directly downregulated by CTLA-4 blockade, although the relative importance of CTLA-4 expression to their function remains controversial.

Figure 2

CTLA-4 blockade and cellular vaccines in poorly immunogenic tumors: the effect of CTLA-4 blockade and vaccination with a GM-CSF expressing cellular vaccine for poorly immuno-genic tumors may depend on the local antigenic milieu and priming history of the T cells. In the nonvaccinated host (A) a direct effect on Treg may predominate due to higher TCR affinities, lower requirements for costimulation and predominance of self-antigen presentation, resulting in a relative expansion of Treg compared to other T-cell populations. The tumor infiltrate is characterized by a relatively high proportion of Treg and very low levels of CD8⁺ T cells. CTLA-4 blockade under these conditions still favors Treg over effector T cells. In the vaccinated host (B) the preferential presentation of tumor-associated antigens in association with high levels of costimulatory molecules allows expansion of effector T-cell populations that can traffic to the tumor, although these cells will now upregulate CTLA-4 expression. Vaccination may be insufficient on its own to eradicate tumor due to the presence of both cell-autonomous and non cell-autonomous inhibitory circuits. The addition of CTLA-4 blockade now tips the balance in favor of the effector population, perhaps aided by the numerical superiority of these cells over tumor-resident Treg resulting in tumor eradication.

Figure 2

CTLA-4 blockade and cellular vaccines in poorly immunogenic tumors: the effect of CTLA-4 blockade and vaccination with a GM-CSF expressing cellular vaccine for poorly immuno-genic tumors may depend on the local antigenic milieu and priming history of the T cells. In the nonvaccinated host (A) a direct effect on Treg may predominate due to higher TCR affinities, lower requirements for costimulation and predominance of self-antigen presentation, resulting in a relative expansion of Treg compared to other T-cell populations. The tumor infiltrate is characterized by a relatively high proportion of Treg and very low levels of CD8⁺ T cells. CTLA-4 blockade under these conditions still favors Treg over effector T cells. In the vaccinated host (B) the preferential presentation of tumor-associated antigens in association with high levels of costimulatory molecules allows expansion of effector T-cell populations that can traffic to the tumor, although these cells will now upregulate CTLA-4 expression. Vaccination may be insufficient on its own to eradicate tumor due to the presence of both cell-autonomous and non cell-autonomous inhibitory circuits. The addition of CTLA-4 blockade now tips the balance in favor of the effector population, perhaps aided by the numerical superiority of these cells over tumor-resident Treg resulting in tumor eradication.

Figure 3

Immunological inhibitory checkpoints: potential therapeutic targets. All of the members of the immunoglobulin superfamily that act as inhibitory checkpoints are potential targets for manipulation in immunotherapies. CD28/CTLA-4:B7.1/B7.2 are centrally important for the initial activation of naïve T cells and regulation of the clonal composition of the responding repertoire following migration of activated dendritic cells to lymphoid organs. As activated effectors traffic back into peripheral tissues they come under the influence of PD1:PD-L1/L2 mediated signaling, both as a result of interactions with tissue macrophages and with ligands expressed on malignant cells. B7-H3 and B7x could be poised to act as the final arbiters of the fate of T effector interactions with nonlymphoid target tissues, and could potentially protect any tumor cells expressing them from cytotoxic T cell mediated killing. The potential for cross-talk between T-cell populations via many of these pathways is complex, particularly as activated T cells can upregulate receptors and/or ligands, which can potentially signal bidirectionally. Blockade of BTLA may remove inhibitory restraints imposed by HVEM-expressing cells, but effects on T–T interactions mediated by blockade of CTLA-4, PD-1/PD-L1, or B7-H3 are also possible.