Multimodal identification of rare potent effector CD8 T cells in solid tumors

Antitumor immunity is driven by CD8 T cells, yet we lack signatures for the exceptional effectors in tumors, amongst the vast majority of CD8 T cells undergoing exhaustion. By leveraging the measurement of a canonical T cell activation protein (CD69) together with its RNA (Cd69), we found a larger classifier for TCR stimulation-driven effector states in vitro and in vivo. This revealed exceptional ‘star’ effectors—highly functional cells distinguished amidst progenitor and terminally exhausted cells. Although rare in growing mouse and human tumors, they are prominent in mice during T cell-mediated tumor clearance, where they engage with tumor antigen and are superior in tumor cell killing. Employing multimodal CITE-Seq allowed de novo identification of similar rare effectors amidst T cell populations in human cancer. The identification of rare and exceptional immune states provides rational avenues for enhancement of antitumor immunity.