Figure 2.

Treg expansion behind hyper-progressive disease (HPD). (A) Within the tumor, the anti-tumor effects of programmed cell death protein 1 (PD-1) blockade on effector T-cells may be short-lived due to the activation and expansion of Tregs. This could be even more pronounced in tumors that contain higher proportions of PD-1⁺ Tregs relative to T-effector cells. Consequently, tumor cells that escape continue to thrive and proliferate. (B) A similar occurrence may take place in the lymphoid organs where a more active Treg population resists fresh generation of anti-tumor T-effector cells. As anti-tumor immunity wanes, tumor progresses unhindered and may even accelerate in the form of HPD. (C) At the cellular level, increased TCR signaling in Tregs devoid of PD-1 signaling may drive increased calcium influx and adenosine triphosphate (ATP) production, which in turn elevates cAMP generation and transfer into Tconv cells. Consequently, TCR stimulation in Tconv cells could still be subdued by the PKA:Csk despite absence of PD-1 inhibitory signals.