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.
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.
|Linch, Stefanie N; Kasiewicz, Melissa J; McNamara, Michael J et al. (2016) Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Proc Natl Acad Sci U S A 113:E319-27|
|Linch, Stefanie N; McNamara, Michael J; Redmond, William L (2015) OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal. Front Oncol 5:34|
|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|