Tumor-specific CD8 T cell peripheral tolerance can be a major barrier to the generation of potent anti- tumor immunity. Recent studies have begun to examine whether signaling through co-stimulatory molecules can sufficiently boost the immune response to reverse tumor-specific tolerance and promote anti-tumor immunity. To this end, our laboratory and others have focused on the mechanisms through which ligation of the OX40 (CD134) co-stimulatory molecule, a member of tumor necrosis factor receptor (TNFR) super-family, augments CD4 and CD8 T cell expansion, differentiation, and survival. Importantly, several studies have also shown that OX40 is expressed on T cells isolated from the tumor-draining lymph nodes of tumor-bearing hosts and that OX40 engagement can boost anti-tumor immunity in vivo. OX40-mediated signaling has also been shown to overcome peptide-induced CD4 T cell anergy. Recently, we demonstrated that OX40 ligation could restore the function of anergic tumor-reactive CD8 T cells in vivo. Although anti-OX40 therapy led to partial tumor regression, the tumors ultimately recurred. Thus, understanding the mechanisms regulating the induction of tumor-specific anergy may lead to the development of new therapeutic strategies to enhance CD8 T cell-mediated anti-tumor immunity.
In Aim I of this proposal, we will investigate the mechanisms by which the common gamma chain (gc) cytokines IL-2 and IL-4 regulate OX40 receptor expression on CD8 T cells including the molecular mechanisms regulating activation of the OX40 promoter.
In Aim II, we will determine the molecular mechanisms by which tumors induce CD8 T cell anergy and test the hypothesis that combined anti-OX40/gc cytokine therapy can restore the function of anergic CTL in tumor-bearing hosts.
Aim III seeks to test the hypothesis that anti-OX40 therapy can enhance the differentiation of endogenous tumor-specific CD8 T cells in mice with spontaneously arising prostate cancer and to test whether anti-OX40 therapy promotes the differentiation of tumor-reactive CD8 T cells in cancer patients that are currently being treated with an agonist anti-OX40 mAb in a phase I clinical trial at the EACRI. Taken together, these studies will provide insight into the mechanisms regulating OX40 expression, the molecular basis of tumor- specific CD8 T cell anergy, and whether anti-OX40 therapy can augment the endogenous CD8 T cell response in both tumor-bearing mice and cancer patients.

Public Health Relevance

These studies will test whether anti-OX40 antibody therapy can enhance CD8 T cell-mediated anti- tumor immunity and enhance the long-term survival of cancer-bearing hosts. Along with the data obtained from an on-going Phase I clinical trial with an anti-OX40 antibody in cancer patients, the results generated in the proposed study will guide the development of future pre-clinical research studies and clinical trials with the potential to directly benefit cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA136678-04
Application #
8470084
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mccarthy, Susan A
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$227,038
Indirect Cost
$73,634
Name
Providence Portland Medical Center
Department
Type
DUNS #
099142093
City
Portland
State
OR
Country
United States
Zip Code
97213
Redmond, William L; Linch, Stefanie N; Kasiewicz, Melissa J (2014) Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol Res 2:142-53
Redmond, William L; Triplett, Todd; Floyd, Kevin et al. (2012) Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. PLoS One 7:e34467