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

Abstract

Radiotherapy (RT) is a key treatment for prostate cancer. However, RT resistance can contribute to treatment failure. Prostate cancer stem cells (PCSCs) are radioresistant. We recently found that fractionated irradiation (FIR) upregulates expression of the immune checkpoint B7-H3 (CD276) on PCSCs and bulk cells in each prostate cancer cell line tested. These findings prompted us to investigate whether B7-H3 targeting chimeric antigen receptor (CAR) T cells, which may abrogate function of an immune checkpoint and mediate lysis of targeted cells, can target RT-resistant PCSCs in vitro and in vivo. B7-H3 expression is naturally higher on PCSCs than bulk prostate cancer cells and cytotoxicity of B7-H3 CAR T cells to PCSCs is more potent than to bulk prostate cancer cells. Furthermore, FIR significantly upregulates B7-H3 expression on PCSCs and bulk prostate cancer cells. The duration of FIR or single-dose irradiation-induced further upregulation of B7-H3 on bulk prostate cancer cells and PCSCs lasts for up to 3 days. B7-H3 CAR T-cell cytotoxicity against FIR-resistant PCSCs at a low effector to target ratio of 1:1 was assessed by flow cytometry and sphere formation assays. Further upregulation of B7-H3 expression by FIR made PCSCs even more sensitive to B7-H3 CAR T-cellmediated killing. Consequently, the FIR and B7-H3 CAR T-cell therapy combination is much more effective than FIR or CAR T cells alone in growth inhibition of hormone-insensitive prostate cancer xenografts in immunodeficient mice. Our work provides a sound basis for further development of this unique combinatorial model of RT and B7-H3 CAR T-cell therapy for prostate cancer.Significance: We demonstrate that FIR significantly upregulates B7-H3 expression by RT-resistant PCSCs and bulk cells; cytotoxicity of B7-H3 CAR T cells to FIR-treated PCSCs is potent and results in significantly improved antitumor efficacy in mice.

Antitumor responses in gastric cancer by targeting B7H3 via chimeric antigen receptor T cells

“…This fully demonstrates the safety and effectiveness of target B7H3 in clinical application. In addition, B7H3 is also currently being explored as a target for CAR-T cell therapy and demonstrated safety and efficacy in mouse mode [ 14 , 15 , 17 , 22 , 23 ]. However, there are no reports on the expression of B7H3 in GC.…”

“…It has been reported that B7-H3 preferentially overexpressed in various tumors but low expression in normal tissues [ 12 ]. As a result, it has been explored as the target of CAR-T cells against solid tumors [ 13 ], including ovarian cancer, esophagus squamous cell carcinoma, pancreatic adenocarcinoma, and brain tumors [ 14 – 17 ]. B7H3 targeted treatment has shown preliminary benefits for patients with tumors and is being evaluated by numerous ongoing clinical trials.…”

MiR-197 Inhibitor Loaded AbCD133@MSNs@GNR Affects the Development of Prostate Cancer Through Targeting ITGAV

“…PCSCs are a small number of cells that drive the occurrence and development of tumor. They play an important role in the development, self-renewal, and drug resistance of PC ( Gratwohl et al, 2002 ; Hermann et al, 2007 ; Miki et al, 2007 ; O’Connor et al, 2014 ; Zhang et al, 2021 ), Research and development of drugs targeting PCSCs is one of the important ways to treat PC.…”

“…Prostate CSCs (PCSCs) were first reported in 2007 ( Miki et al, 2007 ). Studies have shown that PCSCs have self-renewal and unique tumorigenicity in vivo and that PCSCs determine the development of PC; in addition, the resistance of PC to conventional chemotherapy and radiotherapy may be partly due to the existence of PCSCs ( Hermann et al, 2007 ; Huang et al, 2021 ; Navarro-Marchal et al, 2021 ; Zhang et al, 2021 ). Therefore, research and development of drugs targeting PCSCs is one of the important ways to treat PC.…”

Molecular Radiotherapy with 177Lu-Immunoliposomes Induces Cytotoxicity in Mesothelioma Cancer Stem Cells In Vitro

“…It is postulated that tumors are hierarchically organized with a subpopulation of CSCs located at the apex of a pyramid, and these CSCs are responsible for tumor initiation and sustainment through their infinite potential of self-renewal and differentiation into varied progeny forming the bulk of the tumor. Although the origin of CSC remains unclear and controversy arises whether all cancers follow the CSC mode, growing evidence demonstrates that CSCs exist in a wide array of tumors, not only in leukemia [ 13 , 14 ] but also in most solid tumors including breast cancer [ 15 ], ovarian cancer [ 16 ], pancreatic cancer [ 17 , 18 ], colorectal cancer [ 19 ], prostate cancer [ 20 ], glioblastoma [ 21 ], lung cancer [ 22 ], and melanoma [ 23 ].…”