IL-12 conditioning and reconditioning of in vitro activated adoptively transferred CD8+ T cells promotes tissue residency and anti-tumor immunity 3981

Abstract Description The anti-tumor effector functions of in vitro activated tumor-specific CD8+ T lymphocytes (CTL) following adoptive cell transfer (ACT) are well-studied, but less is known about tissue resident memory T cell populations (TRM) formed by ACT. Using multiple murine tumor models and T cell receptor (TCR) transgenic mice, we report that naive T cells activated in vitro by anti-CD3/CD28 in the presence of interleukin-12 (IL-12) robustly populate non-lymphoid tissues (NLT) and adopt canonical TRM phenotypes (CD69+, CD103+, CD49a+) in vivo. Interrogation of these TRM using in vivo assays including parabiosis, alarm therapy, and circulation depletion reveals a key role for ACT derived TRM in tumor protection. To model clinical ACT where isolation of naive tumor-specific T cells is difficult, we reactivated ACT-derived memory CD8+ T cells ex vivo and observed bias toward effector-like circulating memory following in vivo transfer. Use of interleukin-2 (IL-2) to post-expand CTL in vitro prior to ACT dramatically impaired numbers in vivo. While CD69 levels on rare IL-2 expanded CTL populating NLT after ACT appeared normal, expression of CXCR6 and P2RX7 receptors associated with TRM was reduced. Inclusion of IL-12 during reactivation of IL-2 post-expanded CTL restored in vivo expansion and TRM properties, even if IL-12 was absent during initial activation. Enforcing TRM formation and function during in vitro programming may improve the efficacy of CD8+ and other engineered T cells for ACT. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)