VISTA expressed in tumour cells regulates T cell function

Kumuluzi Mulati ¹, Junzo Hamanishi ², Noriomi Matsumura ³, Kenji Chamoto ⁴, Nathan Mise ⁵, Kaoru Abiko ¹, Tsukasa Baba ¹, Ken Yamaguchi ⁶, Naoki Horikawa ¹, Ryusuke Murakami ¹, Mana Taki ¹, Kharma Budiman ¹, Xiang Zeng ¹, Yuko Hosoe ¹, Miyuki Azuma ⁷, Ikuo Konishi ⁶, Masaki Mandai ¹

Affiliations

¹ Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. jnkhmns@kuhp.kyoto-u.ac.jp.
³ Department of Obstetrics and Gynecology, Kindai University, Osaka, Japan.
⁴ Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Department of Environmental Preventive Medicine, Jichi Medical University, Tochigi, Japan.
⁶ Department of Obstetrics and Gynecology, Kyoto Medical Center, Kyoto, Japan.
⁷ Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan.

PMID: 30382166
46 References
47 citations

Abstract

Background: V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune-checkpoint protein. VISTA expression on tumour cells and the associated regulatory mechanisms remain unclear. We investigated VISTA expression and function in tumour cells, and evaluated its mechanism and activity.

Methods: VISTA in tumour cells was assessed by tissue microarray analysis, immunohistochemical staining and western blot. A series of in vitro assays were used to determine the function of tumour-expressed VISTA. In vivo efficacy was evaluated in syngeneic models.

Results: VISTA was highly expressed in human ovarian and endometrial cancers. Upregulation of VISTA in endometrial cancer was related to the methylation status of the VISTA promoter. VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro, and decreased the tumour-infiltrating CD8+ T cells in vivo. Anti-VISTA antibody prolonged the survival of tumour-bearing mice.

Conclusions: This is the first demonstration that VISTA is highly expressed in human ovarian and endometrial cancer cells, and that anti-VISTA antibody treatment significantly prolongs the survival of mice bearing tumours expressing high levels of VISTA. The data suggest that VISTA is a novel immunosuppressive factor within the tumour microenvironment, as well as a new target for cancer immunotherapy.

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