Docetaxel enhances the therapeutic efficacy of PSMA-specific CAR-T cells against prostate cancer models by suppressing MDSCs

Zhang, Xiaokang; Sun, Shishuo; Miao, Yangna; Yang, Yifan; Zhao, Wanxin; Li, Hailong; Wei, Xiaohuan; Huang, Chao; Hu, Xiaolei; Wang, Bixi; Xu, Heng; Zhang, Wei; Gao, Xiaoge; Song, Jingyuan; Zheng, Junnian; Zhang, Qing

doi:10.1007/s00432-022-04248-y

Cited by 10 publications

(4 citation statements)

References 20 publications

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“… 42 (4) Direct elimination. Some therapeutic drugs containing gemcitabine, 43 docetaxel, 44 and 5-fluorouracil 45 have been reported to remove MDSCs. Our data showed that SFN repressed MDSCs immunosuppression by directly inducing apoptosis and constitutes a basis for testing SFN as a strategy to eliminate MDSCs in patients with cancer.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Liu,

Chen,

Guo

et al. 2024

J Immunother Cancer

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BackgroundExtensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME).MethodsWe monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8+T cells in the blood samples from a phase I clinical trial (KY-2021–0350).ResultsIn this study, we elucidated that SFN liberated CD8+T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8+T cells.ConclusionsCollectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8+T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Liu,

Chen,

Guo

et al. 2024

J Immunother Cancer

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“…Chemotherapy has the ability to alter TME and enhance the effectiveness of CAR-T cell therapy. Docetaxel [ 155 ] and gemcitabine [ 156 , 157 ], employed as neoadjuvant therapies, have shown the ability to enhance the effectiveness of GD2 CAR-T cells by decreasing MDSCs in the tumor. Doxorubicin has shown the capacity to boost the activity of CAR-T cells by decreasing the expression of PD-L1 on osteosarcoma cancer cells [ 158 ].…”

Section: Combination Therapies To Enhance Car‑t Cells Efficacymentioning

confidence: 99%

Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors

Chen,

Wang,

Chen

et al. 2024

Cancer Cell Int

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The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors.

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“…A similar reduction in Tregs and impairment of their inhibitory function were also observed with paclitaxel treatment ( 38 , 39 ). In addition, when given as neoadjuvant treatment prior to CAR-T cell infusion, docetaxel was found to enhance the PSMA-CAR-T cell efficacy in prostate cancer mouse models, by reducing MDSCs in the tumor ( 54 ). Similarly, paclitaxel has also been found to reduce the tumor-infiltrating MDSCs and restore effector functions of CD8 + T cells ( 40 ).…”

Section: How Can Chemotherapy Be Used In Conjunction With Car-t Cell ...mentioning

confidence: 99%

Combining chemotherapy with CAR-T cell therapy in treating solid tumors

et al. 2023

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Chemotherapy has long been a standard treatment for a wide range of malignancies, where patients typically undergo multiple rounds of chemotherapy regimens to control tumor growth. In the clinic, the chemotherapy drugs cyclophosphamide and fludarabine are commonly used prior to Chimeric Antigen Receptor T (CAR-T) cell therapy to lymphodeplete and improve CAR-T cell engraftment. In this review, we discuss the use of chemotherapy in combination with CAR-T cell therapy. We also show that chemotherapy can deplete immunosuppressive cells, promote a pro-inflammatory tumor microenvironment, disrupt tumor stroma, and improve CAR-T cell recruitment to the tumor. Although the combination of chemotherapy plus CAR-T cell therapy is promising, certain aspects of chemotherapy also pose a challenge. In addition, the combined therapeutic effect may be heavily dependent on the dose and the treatment schedule. Thus, we also discussed the obstacles to effective clinical outcomes of the combination therapy.

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Docetaxel enhances the therapeutic efficacy of PSMA-specific CAR-T cells against prostate cancer models by suppressing MDSCs

Cited by 10 publications

References 20 publications

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors

Combining chemotherapy with CAR-T cell therapy in treating solid tumors

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Docetaxel enhances the therapeutic efficacy of PSMA-specific CAR-T cells against prostate cancer models by suppressing MDSCs

Cited by 10 publications

References 20 publications

Sulforaphane activates CD8+T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Sulforaphane activates CD8+T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors

Combining chemotherapy with CAR-T cell therapy in treating solid tumors

Contact Info

Product

Resources

About

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’

Sulforaphane activates CD8⁺T cells antitumor response through IL-12RB2/MMP3/FasL-induced MDSCs apoptosis’