Potentiating vascular-targeted photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer

Abstract

2019) Potentiating vascular-targeted photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer, OncoImmunology, 8:6, e1581528, ABSTRACT Vascular-targeted photodynamic therapy (VTP) induces rapid destruction of targeted tissues and is a promising therapy for prostate cancer. However, the resulting immune response, which may play an important role in either potentiating or blunting the effects of VTP, is still incompletely understood. Myeloid cells such as myeloid-derived suppressor cells (MDSCs) and macrophages are often found in tumors and are widely reported to be associated with cancer angiogenesis, tissue remodeling, and immunosuppression. These cells are also known to play a critical role in wound-healing, which is induced by rapid tissue destruction. In this study, we investigated the effects of VTP on the recruitment of tumorinfiltrating myeloid cells, specifically MDSCs and tumor-associated macrophages (TAMs), in the Myc-Cap and TRAMP C2 murine prostate cancer models. We report that VTP increased the infiltration of myeloid cells into the tumors, as well as their expression of CSF1R, a receptor required for myeloid differentiation, proliferation, and tumor migration. As anti-CSF1R treatment has previously been used to deplete these cells types in other murine models of prostate cancer, we hypothesized that combining anti-CSF1R with VTP therapy would lead to decreased tumor regrowth and improved survival. Importantly, we found that targeting myeloid cells using anti-CSF1R in combination with VTP therapy decreased the number of tumor MDSCs and TAMs, especially M2 macrophages, as well as increased CD8 + T cell infiltration, decreased tumor growth and improved overall survival. These results suggest that targeting myeloid cells via CSF1R targeting is a promising strategy to potentiate the anti-tumor effects of VTP. ARTICLE HISTORY

Prostate carcinogenesis: inflammatory storms

“…Whilst there is controversy over whether obesity increases the risk of developing PCa overall, obesity, weight gain, and the metabolic syndrome have been significantly associated with increase biochemical recurrence risk after primary prostatectomy, more aggressive disease, and increased PCa-specific mortality 8,45,50,51 . This is of particular clinical relevance since a main side effect of androgen deprivation therapy (ADT) is a metabolic syndrome with associated weight gain.…”

Tissue Factor-Targeted “O2-Evolving” Nanoparticles for Photodynamic Therapy in Malignant Lymphoma

“…Finally, the long-term curative features and the safety of CENPs combined with PDT remain major concerns. A study in a preclinical mouse model of prostate cancer demonstrated that vPDT increased the influx of immunosuppressive myeloid cells in tumors, which would suppress adaptive immune responses against remaining surviving tumors cells (34). Based on the finding, vPDT might be utilized in combination with immunotherapy (e.g., anti-CSF1R treatment) for triggering a long-lasting treatment response.…”

Tumor irradiation combined with vascular-targeted photodynamic therapy enhances anti-tumor effects in preclinical prostate cancer

“…VTP has distinct advantages as a form of focal therapy; the technique has been evaluated in phase-III randomized clinical trial (28), and it can anatomize treatment such that it conforms to the malignant lesion along with a margin of normal tissue within the prostate gland, preserving urinary and sexual function. Pre-clinical studies in PCa models have demonstrated that VTP may be successfully combined with ADT (47), a 111 In-DOTA-AR bombesin antagonist (48), and anti-macrophage colonystimulating factor (anti-CSFR1) (49), however VTP has not been investigated in close sequential combination with FRT. VTP has been demonstrated to be safe and effective in patients with recurrent PCa following FRT however the patients in these early phase clinical trials received FRT and VTP with a considerable interval of several years.…”