Miles H. Linde

Chimeric antigen receptor T (CAR T) cell therapy has shown limited synergy with immune checkpoint inhibitors, but the mechanisms underlying resistance remain unclear. Stemlike T cells coexpressing programmed cell death protein 1 (PD-1) and T cell factor 1 (TCF1) mediate responses to PD-1–PD-L1 (programmed death ligand 1) blockade and are maintained by major histocompatibility complex (MHC)–dependent interactions with dendritic cells in lymphoid tissues. Because CAR T cells recognize intact antigen rather than peptide-MHC, their activation is restricted to tumors, potentially limiting maintenance of this critical subset. In murine models of lung cancer, CAR T cells down-regulated TCF1, became exhausted, and were not enhanced by PD-L1 blockade. Overexpression of the transcription factor c-Jun increased intratumoral PD-1 ⁺ TCF1 ⁺ CAR T cells but did not prevent exhaustion, given that PD-1 induced posttranscriptional c-Jun down-regulation. PD-L1 blockade restored c-Jun levels, markedly increased CAR T cells, and enabled near-complete tumor clearance, revealing a mechanism by which MHC-independent CAR T cells can be engineered to overcome resistance to PD-1–PD-L1 blockade.

In vivo TR-APC induction drives oligoclonal T cell expansion

In vivo TR-APC induction results in no observable off-target toxicity

Summary of clinical features of primary B-ALL specimens

In vivo TR-APC induction results in expansion of activated and memory T cells, and decreased frequency of Tregs

Primary B-ALL TR-APCs can be generated via exogenous cytokine stimulation

Primary B-ALL-derived TR-APCs activate T cells in an MHC-restricted manner according to the inflammatory milieu

In vivo doxycycline administration results in significant TR-APC induction throughout tumors

TR-APC induction results in inflammatory rewiring of the tumor microenvironment.

In vitro re-exposure of T cells from surviving mice demonstrates TR-APC-mediated generation of tumor-specific memory.