Abstract
Prostate immune system plays a critical role in the regulation of prostate cancer development regarding androgen-deprivation therapy (ADT) and/or immunotherapy (vaccination). In this study, we developed a mathematical model to explore the interactions between prostate tumor and immune microenvironment. This model was used to predict treatment outcomes for prostate cancer with ADT, vaccination, Treg depletion and/or IL-2 neutralization. Animal data were used to guide construction, parameter selection, and validation of our model. Our analysis shows that Treg depletion and/or IL-2 neutralization can effectively improve the treatment efficacy of combined therapy with ADT and vaccination. Treg depletion has a higher synergetic effect than that from IL-2 neutralization. This study highlights a potential therapeutic strategy in effectively managing prostate tumor growth and provides a framework of systems biology approach in studying tumor-related immune mechanism and consequent selection of therapeutic regimens.
Highlights
Prostate immune system plays a critical role in the regulation of prostate cancer development regarding androgen-deprivation therapy (ADT) and/or immunotherapy
Lymphoid compartment is used as a representative of the prostate-draining lymph nodes and spleen, and blood vessel compartment for tumor-immune communication between prostate compartment and lymphoid compartment was not modeled for simplicity
Our analysis showed that the treatment efficacy of Treg depletion was higher than that from IL-2 neutralization using tumor size as outcomes
Summary
Prostate immune system plays a critical role in the regulation of prostate cancer development regarding androgen-deprivation therapy (ADT) and/or immunotherapy (vaccination). We developed a mathematical model to explore the interactions between prostate tumor and immune microenvironment This model was used to predict treatment outcomes for prostate cancer with ADT, vaccination, Treg depletion and/or IL-2 neutralization. Androgen deprivation showed that removal of androgen in male mice increased lymphopoiesis, renewed thymopoiesis, and enhanced immune responses[10,11] These data suggest that it would be beneficial to prostate cancer patients using combined therapeutic immunotherapy with androgen deprivation. We have developed a prostate-specific Pten−/− mouse model and data analysis showed that this mouse model mimicked the scenario of progressive PCa well[12] Both effector (CTLs: cytotoxic T lymphocytes) and inhibitory (Tregs: regulatory T cells) immune mechanisms were amplified by surgical castration (ADT)[13,14,15]. Depletion of Treg or neutralization of IL-2 has potentials in enhancing therapeutic efficacy of combined therapy with ADT and immunotherapy for PCa
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