Fig. 6. Bypassing tumor immune suppression mechanisms with a synthetic IL-2 delivery circuit.

(A) Standard CAR/TCR T cell activity in suppressive microenvironments is limited by inhibition of T cell activation, minimal production of IL-2, and consumption of IL-2 by competing native cells (sinks). Activation of both TCR and cytokine signaling, required for the full T cell response (AND gate), is blocked at these steps.

(B) Creating a bypass channel for IL-2 production that is independent of CAR/TCR activation can overcome key suppressive steps. New circuits allow initiation of T cell activation via synergistic TCR/cytokine stimulation, leading to positive feedback, T cell activation, proliferation, and efficient killing of tumor cells. The synthetic circuit reconstitutes the key requirements for a strong T cell response in a manner that bypasses key suppressive bottlenecks.

(C) Schematic differences between autocrine and paracrine IL-2 signaling in the presence of IL-2 consumers. An autocrine IL-2 circuit provides preferential spatial access to self-made IL-2 in comparison to a paracrine IL-2 circuit, where CAR T cells must compete with other IL-2 consumers (Tregs or T-naive cells).

(D) An autocrine IL-2 leads to preferential expansion of IL-2 producers (through T cell activation and upregulation of CD25) in contrast in a paracrine circuit IL-2 producers compete on equal or lesser footing with IL-2 consumers and are not selectively enriched limiting total IL-2 produced and failing to accumulate enough IL-2 to overcome thresholds required for T cell activation.