IL-2 and CD40L can establish and sustain a human B cell-mediated immune regulatory network

This preprint reports that IL-2 and CD40L drive class-switched memory B cells to a TIGIT-positive immunosuppressive phenotype which suppresses T cell mediated inflammation in a xenogeneic acute graft-versus-host disease model, and proposes TIGIT-positive B cell therapy for inflammatory disease. The Claidex graph holds four TIGIT failures: two Phase 3 efficacy failures in non-small cell lung carcinoma, ociperlimab-tigit-advantig-302-nsclc-class-failure and tiragolumab-tigit-adjuvant-nsclc-phase3-class-efficacy-failure, a Phase 2 strategic termination in BCG-unresponsive bladder cancer, vibostolimab-favezelimab-tigit-bcg-unresponsive-nmibc-keynote-057-phase2-strategic-termination, and a Phase 3 safety termination in adjuvant melanoma, vibostolimab-pembrolizumab-tigit-adjuvant-melanoma-keyvibe-010-phase3-safety-termination. Those programs tested TIGIT blockade to release antitumour immunity, whereas this preprint exploits TIGIT-driven suppression in the opposite therapeutic direction, so the clinical record does not contradict the biology reported here. What the record does establish is that TIGIT engagement in humans has repeatedly failed to produce the immunological effect its proponents predicted at Phase 3 scale, which is a reason to require functional evidence rather than surface marker expression before advancing a TIGIT-positive cell therapy.