Potential models of how immune checkpoint blockade restores positive costimulation and modulates T-cell activity. Potential models of how immune checkpoint blockade restores positive costimulation and modulates T-cell activity. Three non–mutually exclusive theoretical models of how checkpoint blockade regulates the strength of positive costimulation and enhances antitumor immunity. Distinguishing these models will have significant implications for the types and specificities of T cells that are functionally essential for therapeutic efficacy. A, In the first model, checkpoint blockade restores the positive costimulatory signaling to levels similar to those reached prior to attenuation (e.g., by PD-1 or CTLA4). Presumably, in this model, enhanced efficacy due to checkpoint blockade would be primarily derived from an increase in the number of activated and cytolytic T cells. B, In the second model, increased positive costimulation due to blockade of negative costimulatory molecules lowers the effective threshold required for TCR signal strength. This in effect would allow for activation and expansion of weaker T-cell clones (i.e., low-affinity, low-avidity), which are normally restrained. C, In the third model, checkpoint blockade leads to an increase in positive costimulatory signals beyond levels that are achieved in normal scenarios. In this model, enhanced efficacy could be derived from increased number of activated T cells and/or acquisition of new or enhanced functional properties due to super physiologic levels of costimulatory signaling. Spencer C. Wei et al. Cancer Discov 2018;8:1069-1086 ©2018 by American Association for Cancer Research