2. Academic Validation
  3. Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma

Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma

  • Oral Oncol. 2016 Jun:57:54-60. doi: 10.1016/j.oraloncology.2016.04.005.
Yuta Kondo 1,  Tatsukuni Ohno 2,  Naoto Nishii 2,  Kiyoshi Harada 3,  Hideo Yagita 4,  Miyuki Azuma 5
Affiliations

Affiliations

  • 1 Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8547, Japan; Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8547, Japan.
  • 2 Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8547, Japan.
  • 3 Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8547, Japan.
  • 4 Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
  • 5 Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8547, Japan. Electronic address: miyuki.mim@tmd.ac.jp.
PMID: 27208845 DOI: 10.1016/j.oraloncology.2016.04.005
Abstract

V domain-containing Ig suppressor of T-cell activation (VISTA)/PD-1H is a novel immune checkpoint molecule for regulating T-cell activation. We examined the effects of anti-VISTA mAb monotherapy and combination therapy with CTLA-4 or PD-1 blockade in a squamous cell carcinoma (SCCVII) model. VISTA monotherapy did not show clear tumor growth regression, but efficiently induced CD8(+) T cell activation by converting resting and exhausted cells into functional effector cells. VISTA monotherapy did not inhibit recruitment of regulatory T cells (Tregs) in the tumor microenvironment (TME). As an additional treatment to VISTA, CTLA-4 blockade, but not PD-1 blockade, elicited further tumor regression. The CTLA-4 and VISTA combination efficiently inhibited Treg recruitment and increased the ratios of both CD8 T/Treg and CD4 conventional T (Tcon)/Treg in the TME, whereas the PD-1 and VISTA combination dramatically increased tumor-recruiting CD8(+) T cells, but markedly reduced the Tcon/Treg ratio. Our results demonstrate that VISTA blockade efficiently converts CD8(+) T cells into functional effector T cells, but is not sufficient to regress tumor growth due to weak Treg suppression in the TME. Our results suggest that combined CTLA-4 and VISTA blockade is more efficacious than combined PD-1 and VISTA blockade for tumors like head and neck squamous cell carcinoma in which Treg-mediated immune regulation is dominant.

Keywords

CTLA-4; Head and neck squamous cell carcinoma; Immune checkpoint inhibitor; Immunotherapy; PD-1; Tumor microenvironment; VISTA.

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