Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
Interleukin-2 (IL2) was among the earliest reagents used for cancer immunotherapy due to its ability to support the survival and function of tumor-reactive T cells. However, treatment with IL2 is accompanied by off-target toxicity and low response rates in patients. In mouse models, these issues are largely overcome when IL2 is administered as a cytokine/antibody complex (IL2c). The complex has a longer serum half-life and can be designed for preferential cytokine delivery to specific cells of interest. Early studies showed IL2c could boost antitumor immunity in mice by activating tumor-reactive CD8+T cells. But such functional T cells are often limited in the tumor microenvironment, where instead unresponsive tolerant T cells are eventually eliminated by apoptosis, representing a major obstacle to the success of cancer immunotherapy. We found that IL2c treatment rescued tumor-specific CD8+T cells from a state of established tolerance, providing effective immunotherapy in tumor-bearing mice. Expression of the transcription factor T-bet was necessary to drive intratumoral IFNγ production and effector activity by T cells rescued with IL2c. Furthermore, IL2c promoted T-bet expression in human CD4+and CD8+T cells in humanized tumor-bearing mice, but also increased the frequency of Foxp3+regulatory T cells. Our study reveals a novel role for IL2c as a powerful immunotherapeutic reagent capable of reversing tolerance in tumor-reactive T cells, and provides the first evidence that IL2c influences human T cells in vivo, highlighting the translational potential to modulate human antitumor immune responses. Cancer Immunol Res; 4(12); 1016-26. ©2016 AACR.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
Lauryn E
LE
Klevorn
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
Melissa M
MM
Berrien-Elliott
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
Jinyun
J
Yuan
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
Lindsey M
LM
Kuehm
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
Gregory D
GD
Felock
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
Sean A
SA
Crowe
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri. rteague@slu.edu.|Alvin J. Siteman NCI Comprehensive Cancer Center, St. Louis, Missouri.
Ryan M
RM
Teague
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D007376:Interleukin-2 / Q000276:immunology*; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D000906:Antibodies; C508594:IL2 protein, human; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell