BACKGROUND: The combined use of hormone therapy (HT) and radiation therapy (RT) in the clinical setting has lead to improved outcomes in prostate cancer. However, the basis for potential synergy between these two modalities is not well understood. One possible mechanism could be the induction of tumour-specific immunity, since HT has been shown to induce T cell infiltration of human prostate tumours while RT creates an inflammatory milieu at the tumor site.
PURPOSE: To test the hypothesis that HT and RT induce tumor-specific autoantibody and T cell responses that may delay or prevent tumour recurrence.
METHODS: Two Shionogi tumours were established in each of 16 male DD/S mice. Mice were then castrated to induce regression of both tumours. After regression, RT was applied to one tumour region in a subset of mice. Control mice received no radiation. Mice were monitored for recurrence of the non-irradiated tumour, as well as the development of tumor-specific autoantibody responses. In parallel, serological analysis was conducted on serum collected from 74 prostate cancer patients before, during and after HT and RT. Western blotting and SEREX antigen arrays were used to assess whether HT and/or RT induced tumor-specific autoantibody responses in patients relative to 27 age-matched, cancer-free controls.
RESULTS: In the Shionogi model, time to recurrence of the non-irradiated tumour was 38.3 days in the irradiated mice vs. 30.2 days in the control mice, consistent with the induction of a systemic anti-tumour immune response. Indeed, the HT+RT regimen induced an autoantibody response to a ~40 kDa protein in 9/16 (56%) of mice, which correlated with delayed tumour recurrence. We cloned three candidate antigens underlying the autoantibody response, including SH3GLB1, PABPN1 and MDH1. In human patients, treatment-associated autoantibody responses were observed in 15/52 (28.8%) of patients undergoing HT +/or RT, compared to 2/27 cancer-free controls (p=0.028). In 4 individuals, the underlying antigens were cloned by SEREX, and included SDCCAG1, ODF2, PARP1 and CEP78. We are currently investigating whether treatment-induced autoantibody responses are accompanied by T cell responses in both the Shionogi mouse model and human patients.
CONCLUSIONS: HT and RT induce antigen-specific autoantibody responses in a significant proportion of mice with Shionogi tumours and human prostate cancer patients. In the Shionogi model, this immune response correlated with delayed recurrence of both the irradiated and distal non-irradiated tumours. Thus, anti-tumor immunity may contribute to the therapeutic effects of HT and RT, a phenomenon that could potentially be enhanced with the use of immunomodulatory agents.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA