The influence of host immunity on outcomes following hormone therapy for cancer
Date
2008-04-28T16:47:14Z
Authors
Hahn, Sara
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
BACKGROUND: We have recently shown that standard treatments for prostate cancer,
specifically hormone therapy (HT) and radiation therapy, induce antigen-specific immune responses in human patients. However, the contribution of these antigen-specific
immune responses to clinical outcomes is not known.
HYPOTHESIS: HT induces tumour-specific antibody and T cell responses that delay or
prevent tumour recurrence.
METHODS: We utilized the androgen-dependent Shionogi tumour cell line. Male DD/S mice bearing established Shionogi tumours (~64 mm2) were castrated to induce tumour regression, similar to HT in human prostate cancer patients. Control mice were not castrated. Mice were monitored for tumour recurrence. Tumour-specific antibody
responses were measured by immunoblot, and T cell responses by ELISPOT and immunohistochemistry. Tumour-specific antigens were identified by serological
screening of a cDNA expression library (SEREX).
RESULTS: Following castration, 32/33 mice experienced complete tumour regression,
while the remaining mouse experienced partial tumour regression. Of the 32 mice that
underwent complete regression, 72% (23/32) experienced tumour recurrence 3-70 days
post-castration, while the remaining 28% (9/32) remained tumour-free for the duration of the experiment until they were sacrificed for analysis (64-86 days post-castration).
Shionogi tumours became heavily infiltrated by CD3+ T cells between 7-14 days post-castration, after which T cell infiltrates became progressively more sparse. Castration induced antibody responses to one or more tumour proteins in approximately one third of mice with an average latency of 21 days. The most common antibody response was
against poly(A) binding protein, nuclear 1 (PABPN1). Interestingly, 71% (17/24) of
mice with recurrent tumours had an antibody response against PABPN1, whereas only 11% (1/9) of mice that remained tumour-free had a PABPN1-specific antibody response. Put another way, the mean tumour-free interval for those mice that had a PABPN1 antibody response was approximately 25 days compared to approximately 63 days for those mice that did not have a PABPN1 antibody response. However, we found a moderate correlation between the timing of the PABPN1-specific antibody response and growth rate of the recurrent tumour, such that if a mouse had a PABPN1-specific antibody response that occurred shortly after castration, it was more likely to have a slower growing recurrent tumour. IFN-γ ELISPOT assays revealed that castration also induced a PABPN1-specific T cell response that persisted for the duration of the
experiment (up to 92 days post-castration). Unexpectedly, this T cell response was
exceedingly stronger in recurrent mice versus non-recurrent mice and was accompanied
by splenomegaly in recurrent mice. Anti-CD3 staining of the recurrent tumours showed
that the CD3+ T cells were confined to the periphery and stroma of the tumours.
CONCLUSIONS: In the androgen-dependent murine Shionogi carcinoma model, HT induces robust antibody and T cell responses to PABPN1 that are associated with unfavourable outcomes. To determine why those mice that do not have PABPN1-specific antibody and T cell responses have better outcomes, we will further delineate the T cell response with respect to CD4+ versus CD8+ subpopulations. Additionally, we will investigate the use of immunomodulatory agents to amplify host CD8+ T cell responses and thereby improve the therapeutic effects of HT.
Description
Keywords
Tumour immunology