Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.

<p>Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch–induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.</p>

Synthetic cytokine circuits that drive T cells into immune-excluded tumors

Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA.

Department of Medicine, University of California San Francisco; San Francisco, CA 94158, USA.

Department of Cellular and Molecular Pharmacology, University of California San Francisco; San Francisco, CA 94158, USA.

Biophysics Graduate Program, University of California San Francisco; San Francisco, CA 94158, USA.

Department of Microbiology and Immunology, University of California San Francisco; San Francisco, CA 94158, USA.

Department of Molecular and Cellular Physiology and Structural Biology, Howard Hughes Medical Institute, Stanford University; Stanford, USA.

Department of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94158, USA.

Parker Institute for Cancer Immunotherapy, University of California San Francisco; San Francisco, CA 94158, USA.

Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco; San Francisco, CA 94158, USA.