In situ vaccination combined with androgen ablation and regulatory T-cell depletion reduces castration-resistant tumor burden in prostate-specific pten knockout mice.
There is no effective treatment for prostate cancer arising after androgen ablation. Previous studies have analyzed the short-term effects of androgen ablation on the immune system and suggest an abatement of immune suppression by hormone removal. Because castration-resistant disease can arise years after treatment, it is crucial to determine the duration of immune potentiation by castration. Because immunotherapeutic efficacy is determined by the balance of immune cell subsets and their location within the tumor, we assessed the acute and chronic effect of androgen ablation on the localization of T-cell subsets within castration-resistant murine prostate cancer. We observed a transient increase in CD4+ and CD8+ T-cell numbers at the residual tumor after androgen ablation. More than 2 months later, regulatory T cells (Treg) were increasingly found within prostate epithelium, whereas CTLs, which were evenly distributed before androgen ablation, became sequestered within stroma. Anti-CD25 antibody administration along with castration enhanced CTL access to cancerous glands but did not increase effector function. Intraprostatic injection of LIGHT-expressing tumor cells increased the proportion of CD8+ T cells with functional capacity within the cancerous gland. In addition, Treg depletion within the tumor was enhanced. Together, these manipulations significantly reduced castration-resistant tumor burden. Thus, our results indicate that immune modulations, which prevent Treg accumulation and augment effector cell infiltration of prostatic epithelium, may be effective in reducing tumor burden or preventing tumor recurrence after androgen ablation therapy.
Akins
Elizabeth J
EJ
Department of Pathology-Tumor Biology, Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157-1092, USA.
Moore
Miranda L
ML
Tang
Shuai
S
Willingham
Mark C
MC
Tooze
Janet A
JA
Dubey
Purnima
P
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D000728:Androgens / Q000172:deficiency; D000818:Animals; D016516:CD4-CD8 Ratio; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D012509:Sarcoma / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000096:biosynthesis / Q000276:immunology*
D000728:Androgens; D019496:Cancer Vaccines; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
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