Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells

Area of Science:

• Oncology
• Immunotherapy
• Cancer Stem Cell Biology

Background:

• Radiotherapy (RT) is a primary treatment for prostate cancer, but resistance limits its efficacy.
• Prostate cancer stem cells (PCSCs) exhibit inherent radioresistance, contributing to treatment failure.
• Fractionated irradiation (FIR) was observed to upregulate B7-H3 (CD276) expression on PCSCs and bulk prostate cancer cells.

Purpose of the Study:

• To investigate the efficacy of B7-H3 targeting chimeric antigen receptor (CAR) T cells against RT-resistant PCSCs.
• To determine if FIR-induced upregulation of B7-H3 enhances CAR T-cell targeting of PCSCs.
• To evaluate the combined therapeutic potential of FIR and B7-H3 CAR T-cell therapy in prostate cancer models.

Main Methods:

• Assessing B7-H3 expression on PCSCs and bulk prostate cancer cells following FIR.
• Evaluating B7-H3 CAR T-cell cytotoxicity against FIR-treated PCSCs using flow cytometry and sphere formation assays.
• Testing the efficacy of combination FIR and B7-H3 CAR T-cell therapy in hormone-insensitive prostate cancer xenograft models.

Main Results:

• FIR significantly upregulates B7-H3 expression on both PCSCs and bulk prostate cancer cells, with effects lasting up to 3 days.
• B7-H3 CAR T cells exhibit potent cytotoxicity against FIR-treated PCSCs, with enhanced killing observed at low effector-to-target ratios.
• The combination of FIR and B7-H3 CAR T-cell therapy demonstrated superior inhibition of tumor growth compared to either monotherapy in preclinical models.

Conclusions:

• FIR enhances the susceptibility of radioresistant PCSCs to B7-H3 CAR T-cell therapy by increasing B7-H3 expression.
• Combined FIR and B7-H3 CAR T-cell therapy represents a promising strategy for overcoming RT resistance in prostate cancer.
• This combinatorial approach warrants further investigation for clinical development in prostate cancer treatment.