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
| Autor: | Brian T. Fife, Matthew F. Mescher, Christopher G. Tucker, Jason S. Mitchell, Lovejot M. Singh, Joseph C. Wilson, Alexander J. Dwyer, Lalit K. Beura, Brandon J. Burbach, Tijana Martinov |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
T cell Immunology Cell- and Tissue-Based Therapy Melanoma Experimental Receptors Antigen T-Cell Autoimmunity chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Lymphocyte Activation medicine.disease_cause Immunotherapy Adoptive Article Cell therapy Mice 03 medical and health sciences 0302 clinical medicine Antigens Neoplasm Cell Line Tumor medicine Animals Immunology and Allergy Cell Proliferation Chemistry Melanoma Membrane Proteins medicine.disease Interleukin-12 Peptide Fragments Mice Inbred C57BL Cytokine medicine.anatomical_structure Interleukin 12 Cancer research CD8 Ex vivo 030215 immunology |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2000007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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