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Enhancement of CD70-specific CAR T treatment by IFN-γ released from oHSV-1-infected glioblastoma

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Abstract

Even with progressive combination treatments, the prognosis of patients with glioblastoma (GBM) remains extremely poor. OV is one of the new promising therapeutic strategies to treat human GBM. OVs stimulate immune cells to release cytokines such as IFN-γ during oncolysis, further improve tumor microenvironment (TME) and enhance therapeutic efficacy. IFN-γ plays vital role in the apoptosis of tumor cells and recruitment of tumor-infiltrating T cells. We hypothesized that oncolytic herpes simplex virus-1 (oHSV-1) enhanced the antitumor efficacy of novel CD70-specific chimeric antigen receptor (CAR) T cells by T cell infiltration and IFN-γ release. In this study, oHSV-1 has the potential to stimulate IFN-γ secretion of tumor cells rather than T cell secretion and lead to an increase of T cell activity, as well as CD70-specific CAR T cells can specifically recognize and kill tumor cells in vitro. Specifically, combinational therapy with CD70-specific CAR T and oHSV-1 promotes tumor degradation by enhancing pro-inflammatory circumstances and reducing anti-inflammatory factors in vitro. More importantly, combined therapy generated potent antitumor efficacy, increased the proportion of T cells and natural killer cells in TME, and reduced regulatory T cells and transformed growth factor-β1 expression in orthotopic xenotransplanted animal model of GBM. In summary, we reveal that oHSV-1 enhance the therapeutic efficacy of CD70-spefific CAR T cells by intratumoral T cell infiltration and IFN-γ release, supporting the use of CAR T therapy in GBM therapeutic strategies.

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Availability of data and materials

All data generated in this study are available from the corresponding author on reasonable request.

Abbreviations

CAR:

Chimeric antigen receptor

DAPI:

2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride.

DMEM:

Dulbecco's modified eagle medium

EGFP:

Enhanced green fluorescent protein

GBM:

Glioblastoma

IF:

Immunofluorescence

IFN:

Interferon

IL:

Interleukin

IVIS:

In vivo imaging system

NK:

Natural killer

PBMCs:

Peripheral blood mononuclear cells

PBS:

Phosphate buffer saline

oHSV-1:

Oncolytic herpes simplex virus-1

OVs:

Oncolytic virus

TGF:

Transforming growth factor

TME:

Tumor microenvironment

TNF:

Tumor necrosis factor

trCD27:

Truncated CD27

Treg:

Regulatory T

SME:

Scanning electron microscopy

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Funding

This work was supported by grants from the Beijing Natural Science Foundation Program and Scientific Research Key Program of the Beijing Municipal Commission of Education (KZ202010025034), the Capital’s Funds for Health Improvement and Research (CFH, 2020–1-1071), the National Natural Science Foundation of China (No, 81672478), the Natural Science Foundation of Beijing Municipality (No. 7202020) and the Beijing Laboratory of Biomedical Materials Foundation.

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Authors and Affiliations

  1. Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100070, China

    Guidong Zhu, Junwen Zhang, Qing Zhang, Guishan Jin, Xiaodong Su & Fusheng Liu

  2. Department of Neurosurgery, Beijing Tiantan Hospital Affiliated To Capital Medical University, Beijing, 100070, China

    Guidong Zhu, Junwen Zhang, Qing Zhang, Guishan Jin, Xiaodong Su & Fusheng Liu

  3. Beijing Laboratory of Biomedical Materials, Beijing, 100070, China

    Guidong Zhu, Junwen Zhang, Qing Zhang, Guishan Jin, Xiaodong Su & Fusheng Liu

  4. Shandong Second Provincial General Hospital, Shandong Provincial ENT Hospital, Jinan, 250031, China

    Guidong Zhu

  5. Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing Tongren Hospital, Capital Medical University, Beijing, China

    Sisi Liu

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  1. Guidong Zhu
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Contributions

F.S.L and G.D.Z were responsible for design of the experiments, G.D.Z., J.W.Z and Q.Z performed the experiments, Q.Z., J.W.Z., F.S.L and G.S. J were responsible for acquisition of the data, G.D.Z., Q.Z. and X.D.S analyzed the data and prepared the manuscript, G.D.Z., J.W.Z., Q.Z., G.S.J., X.D.S. and F.S.L wrote the manuscript. All authors have read and approved the final version.

Corresponding author

Correspondence to Fusheng Liu.

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Conflict of interest

The authors declare no conflicts of interest.

Ethics approval and consent to participate

The Experimental Animal Welfare and Ethics Committee of Beijing Tiantan Hospital affiliated to Capital Medical University and approved all the animal experiments. The use of tissue samples from patients with glioblastoma and the peripheral blood of healthy donors were approved by Ethics Committee of Beijing Tiantan Hospital affiliated to Capital Medical University.

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Not applicable. All authors read and approved the manuscript.

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Zhu, G., Zhang, J., Zhang, Q. et al. Enhancement of CD70-specific CAR T treatment by IFN-γ released from oHSV-1-infected glioblastoma. Cancer Immunol Immunother 71, 2433–2448 (2022). https://doi.org/10.1007/s00262-022-03172-x

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