Simultaneous activation of STING and lymphotoxin β receptor potentiates immune checkpoint inhibition and prevents tumor recurrence and metastasis by inducing germinal center B cell responses in TLS 4774

Abstract Description We found that simultaneous activation of innate immune effectors, STING and lymphotoxin-b receptor (LTbR), using their agonists induces intratumoral germinal center B cell responses to generate functional TLS in mouse tumors. STING activation alone was insufficient for inducing TLS; however, when combined with LTbR activation, it improved the fitness of TLS with B cell maturation to IgG-producing long-lived plasma cells and memory cells, increased CD4+T cell recruitment and memory CD8+T cell expansion and shifted the Th2/Th17 balance. This TLS-inducing treatment significantly reduced the tumor size and heightened the efficacy of anti-PD-1 immune checkpoint inhibition, leading to complete cure. When used as neoadjuvant therapy, it prevented tumor recurrence and metastasis indicating the effective immunization against tumors. Using this approach, we show that functional TLS can be induced in different tumor types and anatomical sites—TLS developed in adenocarcinomas and sarcomas in the pancreas, mammary gland, skeletal muscle, and subcutaneous tissues. Mechanistically, the TLS induction by this strategy is T cell dependent, and the anti-tumor activity of the agonists is mediated by both humoral and cellular immunity, involving B cells, T cells, and NK cells. Our study provides a clinically applicable strategy for therapeutic induction of fully functional TLS, which has been a long-waited unmet need for cancer immunotherapy. Funding Sources National Cancer Institute, National Institutes of Health (CA251192, CA125255), Department of Defense (W81XWH2211051), Florida Department of Health (20B01), and Johns Hopkins All Children’s Foundation. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)