Adoptive T Cell Therapy with IL-12–Preconditioned Low-Avidity T Cells Prevents Exhaustion and Results in Enhanced T Cell Activation, Enhanced Tumor Clearance, and Decreased Risk for Autoimmunity
- 1 September 2020
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 205 (5), 1449-1460
- https://doi.org/10.4049/jimmunol.2000007
Abstract
Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield T cells able to home to tumors and effectively kill them. Our previous study demonstrated ex vivo activation in the presence of IL-12–induced optimal CD8+ T cell expansion and melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due to transfer of high-avidity self-specific T cells. In this study, we compared mouse low- and high-avidity T cells targeting the tumor Ag tyrosinase-related protein 2 (TRP2). Not surprisingly, high-avidity T cells provide superior tumor control, yet low-avidity T cells can promote tumor regression. The addition of IL-12 during in vitro expansion boosts low-avidity T cell responsiveness, tumor regression, and prevents T cell exhaustion. In this study, we demonstrate that IL-12–primed T cells are resistant to PD-1/PD-L1–mediated suppression and retain effector function. Importantly, IL-12 preconditioning prevented exhaustion as LAG-3, PD-1, and TOX were decreased while simultaneously increasing KLRG1. Using intravital imaging, we also determined that high-avidity T cells have sustained contacts with intratumoral dendritic cells and tumor targets compared with low-avidity T cells. However, with Ag overexpression, this defect is overcome, and low-avidity T cells control tumor growth. Taken together, these data illustrate that low-avidity T cells can be therapeutically beneficial if cocultured with IL-12 cytokine during in vitro expansion and highly effective in vivo if Ag is not limiting. Clinically, low-avidity T cells provide a safer alternative to high-avidity, TCR-engineered T cells, as IL-12–primed, low-avidity T cells cause less autoimmune vitiligo.Keywords
This publication has 52 references indexed in Scilit:
- Advances in the Treatment of Metastatic Melanoma: Adoptive T-Cell TherapySeminars in Oncology, 2012
- Ex Vivo Interleukin-12-Priming During CD8+ T Cell Activation Dramatically Improves Adoptive T Cell Transfer Antitumor Efficacy in a Lymphodepleted HostJournal of the American College of Surgeons, 2012
- Tumor Vascular Morphology Undergoes Dramatic Changes during Outgrowth of B16 Melanoma While Proangiogenic Gene Expression Remains UnchangedISRN Oncology, 2011
- Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T CellsImmunity, 2011
- Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infectionNature Immunology, 2011
- Improving Adoptive T Cell Therapy by Targeting and Controlling IL-12 Expression to the Tumor EnvironmentMolecular Therapy, 2011
- Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signalNature Immunology, 2009
- Ocular and Systemic Autoimmunity after Successful Tumor-Infiltrating Lymphocyte Immunotherapy for Recurrent, Metastatic MelanomaOphthalmology, 2009
- Melanoma Progression Despite Infiltration by In Vivo-primed TRP-2–specific T CellsJournal of Immunotherapy, 2009
- Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infectionNature Immunology, 2008