In recent years, synthetic immunology has allowed us to probe the complex interactions between immune cells and their environment, and to develop novel strategies for treating diseases. Cell-based immunotherapies, particularly chimeric antigen receptor (CAR) T cells, have made advances in the clinic for treatment of hematological malignancies. However, there is a broader potential for cell-based immunotherapies to impact the treatment of many challenging diseases such as solid tumors or autoimmunity. Immune cells can be engineered with synthetic circuits to carry out more precise molecular recognition and therapeutic action. Synthetic reconstitution of immune signaling by engineering systems from the bottom-up allow us to identify molecular features sufficient to achieve particular sets of behaviors. Here, we engineered T cells using synthetic Notch (synNotch) receptors that induce the local production of therapeutic payloads. First presented is an exploration of T cell circuits that induce the production of pro-inflammatory cytokine IL-2 specifically at the site of a tumor, bypassing tumor suppression to clear challenging solid tumors without inducing systemic toxicity. Second presented is the study of T cell circuits that drive local immune suppression to block off-target CAR T cell toxicity or protect transplants from cytotoxic T cell killing without systemic immune suppression. Together, these studies demonstrate how synthetic T cell circuits can be used to perturb immune microenvironments for therapeutic applications
