A major problem in tumor immunotherapy is the fact that tumor specific CD8 T cells are restrained by self- tolerance and normal mechanisms of immune homeostasis. The goal of this project is to enhance tumor eradication by low avidity CD8 T cells specific for tumor antigens. These experiments will use RIP-Tag2HA mice in which autochthonous insulinomas develop and express a surrogate tumor antigen, the influenza hemagglutinin (HA), and 3 different lines of TCR transgenic mice specific for HA epitopes. Clone 1 and Clone 4 TCR transgenics express TCR derived from CD8 cells that recognized the same Kd restricted epitope of HA with low or high affinity, respectively. SFE TCR transgenics express a CD4 derived TCR specific for a different epitope of HA restricted to I-Ed. Two different experimental strategies will be pursued to enhance tumor eradication.
Aim 1 describes the development of a new type of adjuvant consisting of complexes of IL-2 bound by anti-IL-2 (IL-2c), combined with a well tolerated inflammatory adjuvant, poly(I:C). These synergize to promote tumor eradication by low avidity tumor specific Clone 1 CD8 cells. Experiments under Aim 1 will investigate the molecular basis for the ability of this combination of adjuvants to promote survival and tumor eradication by low avidity, tumor specific CD8 cells. The second strategy is the use of tumor specific CD4 cells to assist low avidity CD8 cells in infiltration and destruction of tumor cells.
Aim 2 will examine why SFE CD4 cells, but not Clone 1 CD8 cells, are efficiently recruited to the tumor milieu, and how CD4 cells promote recruitment of Clone 1.

Public Health Relevance

The goal of cancer immunotherapy is to use our immune system to destroy cancer cells. The goal of this project is to improve cancer vaccines and immunotherapy so that they may be used as a reliable method for treatment of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA057855-21
Application #
8259231
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
1992-08-14
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
21
Fiscal Year
2012
Total Cost
$389,284
Indirect Cost
$183,857
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Bos, Rinke; Sherman, Linda A (2010) CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res 70:8368-77
Wong, S B Justin; Bos, Rinke; Sherman, Linda A (2008) Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol 180:3122-31
Verdeil, Gregory; Marquardt, Kristi; Surh, Charles D et al. (2008) Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy. Proc Natl Acad Sci U S A 105:16683-8
Lyman, Michael A; Nugent, C Thomas; Marquardt, Kristi L et al. (2005) The fate of low affinity tumor-specific CD8+ T cells in tumor-bearing mice. J Immunol 174:2563-72
Redmond, William L; Sherman, Linda A (2005) Peripheral tolerance of CD8 T lymphocytes. Immunity 22:275-84
Redmond, William L; Marincek, Boris C; Sherman, Linda A (2005) Distinct requirements for deletion versus anergy during CD8 T cell peripheral tolerance in vivo. J Immunol 174:2046-53
Lyman, Michael A; Aung, Sandra; Biggs, Judith A et al. (2004) A spontaneously arising pancreatic tumor does not promote the differentiation of naive CD8+ T lymphocytes into effector CTL. J Immunol 172:6558-67
Redmond, William L; Hernandez, Javier; Sherman, Linda A (2003) Deletion of naive CD8 T cells requires persistent antigen and is not programmed by an initial signal from the tolerogenic APC. J Immunol 171:6349-54
Kreuwel, Huub T C; Aung, Sandra; Silao, Cheryl et al. (2002) Memory CD8(+) T cells undergo peripheral tolerance. Immunity 17:73-81
Hernandez, Javier; Aung, Sandra; Marquardt, Kristi et al. (2002) Uncoupling of proliferative potential and gain of effector function by CD8(+) T cells responding to self-antigens. J Exp Med 196:323-33

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