Administration of a glypican‐3 peptide increases the infiltration and cytotoxicity of CD8+ T cells against testicular yolk sac tumor, associated with enhancing the intratumoral cGAS/STING signaling

Author:

Zhao Junfeng12,Qin Le3,He Guorong3,Xie Tiancheng1,Hu Guanghui4,Wang Furan2,Zhong Hongji2,Zhu Jianming2,Xu Yunfei1ORCID

Affiliation:

1. Department of Urology, Shanghai Tenth People's Hospital School of Medicine in Tongji University Shanghai China

2. Department of Pediatrics Surgery Ningbo Women and Children's Hospital Ningbo China

3. Department of Pediatrics Surgery The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China

4. Department of Urology, Renji Hospital School of Medicine in Shanghai Jiaotong University Shanghai China

Abstract

AbstractBackgroundGlypican‐3 (GPC3) is highly expressed in testicular yolk sac tumor (TYST). GPC3 has been evaluated as a cancer vaccine for some types of tumors, but little is known on the effects of GPC3 peptide‐based therapy on TYST. Here, we evaluated the antitumor effect of GPC3144‐152 on TYST and its potential mechanisms.MethodsGPC3144‐152‐specific CD8+ T cells were induced by vaccine immunization and examined by ELISPOT. The CD8+ T cells were purified for testing their cytotoxicity in vitro against TYST cells by CCK‐8 and TUNEL assays and in vivo against tumor growth. The influence of GPC3144‐152 loading and/or cGAS silencing on the tumor growth, apoptosis and cGAS/STING signaling was tested by immunohistochemistry, immunofluorescence, flow cytometry, and Western blot.ResultsVaccination with GPC3144‐152 induced tumor‐specific CD8+ T cells that secreted high levels of IFN‐γ and granzyme B, and had potent cytotoxicity against TYST in a dose‐dependent manner. Adoptive transfer of CD8+ T cells and treatment with GPC3144‐152 significantly inhibited the growth of TYST tumors, but less effective for cGAS‐silenced TYST tumors in vivo. Treatment with GPC3144‐152 enhanced the infiltration of CD8+ T cells into the tumor environment and their cytotoxicity against TYST tumors in vivo by up‐regulating granzyme B and IFN‐β expression, but down‐regulating GPC3 expression in the tumors. Co‐culture of CD8+ T cells with TYST in the presence of exogenous GPC3144‐152 enhanced peptide‐specific CD8+ T‐cell cytotoxicity in vitro, accompanied by enhancing cGAS, γH2AX, TBK1, and IRF3 phosphorylation in TYST cells, but less effective in cGAS‐silenced TYST cells.ConclusionsThese data indicated that GPC3 peptide‐specific CD8+ T cells had potent antitumor activity against TYST tumor, particularly for combined treatment with the peptide, which was partially dependent on the intratumoral cGAS/STNG signaling. GPC3 peptide vaccine may be valuable for the combination treatment of TYST.

Publisher

Wiley

Subject

Cancer Research,Radiology, Nuclear Medicine and imaging,Oncology

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