Cytotoxic CD4 Th1 cells are emerging as a physiologically relevant and therapeutically useful T cell lineage that can successfully target tumors. Until now the cellular and molecular pathways that program their differentiation have been poorly understood. Our preliminary data demonstrates that CD134 (OX40) costimulation induces na?ve self-reactive CD4 T cells to differentiate into cytotoxic Th1 effectors, and the addition of CD137 (4-1BB) costimulation maximizes their clonal expansion. This differentiation process requires IL-2, and the T-box transcription factor Eomesodermin (Eomes). The experimental plan will test if Eomes programs bone fide memory potential. If so, this will help to resolve the recurring controversy regarding the existence and basis of CD4 T cell memory. Perhaps our most unexpected observation is that CD134 plus CD137 dual costimulation-programmed antigen-specific cytotoxic CD4 Th1 cells """"""""imprint"""""""" antigen - inexperienced bystanding T cells with similar functional capacities. We will test if these polyclonal bystander - activated effectors can be exploited to target antigen-loss variant tumor cells that have down-regulated epitopes recognized by specific cytotoxic T cells elicited by immunotherapy, and if these bystander T cells mediate pathogenic side effects associated with immunotherapy. In summary, the proposed experiments will mechanistically dissect how CD134 plus CD137 dual costimulation induces specific and bystander cytotoxic CD4 Th1 cells, and develop therapeutic strategies to harness their potential to control tumor growth that can be translated clinically to treat human cancer patients.

Public Health Relevance

Cytotoxic CD4 Th1 cells are emerging as a therapeutically useful T cell lineage that can target tumors, but up till now the pathways that program their differentiation have been poorly understood. Our preliminary findings reveal that the CD134 (OX40) plus CD137 (4-1BB) costimulatory pathways induce cytotoxic CD4 Th1 cell differentiation, and the proposed work will study the underlying mechanisms as well as develop clinically translatable strategies for using dual costimulation to eradicate tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI094640-01A1
Application #
8292553
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2012-02-15
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$379,747
Indirect Cost
$129,747
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Mittal, Payal; Abblett, Rebecca; Ryan, Joseph M et al. (2018) An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells. J Immunol 200:1513-1526
Ryan, Joseph M; Mittal, Payal; Menoret, Antoine et al. (2018) A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice. Cancer Immunol Immunother 67:605-613
Adler, Adam J; Mittal, Payal; Ryan, Joseph M et al. (2017) Cytokines and metabolic factors regulate tumoricidal T-cell function during cancer immunotherapy. Immunotherapy 9:71-82
Ryan, Joseph M; Wasser, Jeffrey S; Adler, Adam J et al. (2016) Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too? Expert Opin Biol Ther 16:655-74
Tsurutani, Naomi; Mittal, Payal; St Rose, Marie-Clare et al. (2016) Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis. J Immunol 196:124-34
Mittal, Payal; St Rose, Marie-Clare; Wang, Xi et al. (2015) Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy. J Immunol 195:5816-26
Adler, Adam J; Vella, Anthony T (2013) Striving for synergy: how to improve cancer immunotherapy through multiple agonist costimulation. Immunotherapy 5:1271-3
Adler, Adam J; Vella, Anthony T (2013) Betting on improved cancer immunotherapy by doubling down on CD134 and CD137 co-stimulation. Oncoimmunology 2:e22837
St Rose, Marie-Clare; Taylor, Roslyn A; Bandyopadhyay, Suman et al. (2013) CD134/CD137 dual costimulation-elicited IFN-? maximizes effector T-cell function but limits Treg expansion. Immunol Cell Biol 91:173-83