Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

Schematic of the molecular mechanisms of action of CTLA4 and PD-1 blockade. The step-wise progression of T-cell activation, attenuation by normal regulatory mechanisms, and release of such negative regulation by therapeutic intervention using anti-CTLA4 or anti–PD-1 antibodies is outlined (left). In addition to cell-intrinsic enhancement of effector function, several additional mechanisms are thought to contribute to the efficacy of anti-CTLA4 and anti–PD-1 therapy (right). These include antibody-mediated depletion of Tregs, enhancement of T-cell positive costimulation within the tumor microenvironment, blockade of host-derived PD-L1 signals from nontumor cells in the microenvironment (as opposed to tumor cell–derived PD-L1), and blockade of interactions between PD-L1 and B7-1.

Potential cellular mechanisms that mediate tumor rejection in response to combination anti-CTLA4 and anti–PD-1 checkpoint blockade. Multiple non–mutually exclusive models of the cellular mechanisms underlying combination anti-CTLA4 plus anti–PD-1 therapy of action are proposed. Models described from left to right: (i) the same T cells may be targeted at the site of priming, leading to enhanced penetrance of effective blockade (i.e., a greater proportion of target cells receive sufficient signal to increase activation) and/or enhanced costimulatory signals beyond normal limits, (ii) different T-cell populations are targeted within the site of priming, potentially leading to synergistic effects through cell-extrinsic processes (e.g., providing CD4 help to CD8 effector T cells), (iii) the same T cells are targeted but with different spatiotemporal kinetics leading to perhaps prolonged costimulatory signaling, and (iv) different T-cell populations are targeted in different tissues (e.g., PD-1 blockade primarily acting on preexisting tumor-infiltrating CD8 T cells whereas CTLA4 acts on CD4 effector T cells in secondary lymphoid organs). T-cell subsets are denoted as “A” and “B” given that the precise populations that are directly targeted remain to be fully defined, particularly in the context of kinetics of therapy and different tissue sites. Conceptually, T-cell “A” and “B” could, for example, represent particular subsets of tumor-specific CD8 T cells and CD4 effector T cells, respectively. Potential effects are noted below each scenario; however, there is certain to be additional aggregate effects and differences between these models. Only secondary lymphoid organs (e.g., draining lymph node) and tumor are described, but other tissue sites may have functional contributions to this process as well.