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Cytotoxic T lymphocytes (CTL) are antigen-specific effector cells with the ability to eradicate cancer cells in a contact-dependent manner. Metabolic perturbation compromises the CTL effector response in tumor subregions, resulting in failed cancer cell elimination despite the infiltration of tumor-specific CTLs. Restoring the functionality of these tumor-infiltrating CTLs is key to improve immunotherapy. Extracellular adenosine is an immunosuppressive metabolite produced within the tumor microenvironment. Here, by applying single-cell reporter strategies in 3D collagen cocultures in vitro and progressing tumors in vivo, we show that adenosine weakens one-to-one pairing of activated effector CTLs with target cells, thereby dampening serial cytotoxic hit delivery and cumulative death induction. Adenosine also severely compromised CTL effector restimulation and expansion. Antagonization of adenosine A2a receptor (ADORA2a) signaling stabilized and prolonged CTL-target cell conjugation and accelerated lethal hit delivery by both individual contacts and CTL swarms. Because adenosine signaling is a near-constitutive confounding parameter in metabolically perturbed tumors, ADORA2a targeting represents an orthogonal adjuvant strategy to enhance immunotherapy efficacy.

Adenosine A2a Receptor Antagonism Restores Additive Cytotoxicity by Cytotoxic T Cells in Metabolically Perturbed Tumors