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

Yuta Kondo1, Tatsukuni Ohno2, Naoto Nishii2

  • 1Department 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.

Oral Oncology
|May 22, 2016
PubMed

Insights

Anti-VISTA antibody therapy activates CD8+ T cells but needs combination therapy for tumor regression. Combining VISTA blockade with CTLA-4 blockade is more effective than with PD-1 blockade for certain cancers.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Immunotherapy

Background:

  • V domain-containing Ig suppressor of T-cell activation (VISTA) is a novel immune checkpoint molecule regulating T-cell activation.
  • Immune checkpoint inhibitors (ICIs) like anti-CTLA-4 and anti-PD-1 are crucial in cancer therapy.
  • Understanding VISTA's role in the tumor microenvironment (TME) is essential for optimizing cancer immunotherapy.

Purpose of the Study:

  • To evaluate the efficacy of anti-VISTA monoclonal antibody (mAb) monotherapy and combination therapy with CTLA-4 or PD-1 blockade.
  • To investigate the impact of these therapies on T-cell activation and regulatory T cells (Tregs) within the TME.
  • To determine the optimal combination strategy for squamous cell carcinoma (SCCVII) models.

Main Methods:

  • Treatment of a squamous cell carcinoma (SCCVII) mouse model with anti-VISTA mAb monotherapy.
  • Combination therapy using anti-VISTA mAb with either anti-CTLA-4 or anti-PD-1 blockade.
  • Analysis of T-cell populations (CD8+, Tregs, CD4+ conventional T cells) and tumor growth within the TME.

Main Results:

  • VISTA monotherapy enhanced CD8+ T cell activation but did not significantly regress tumor growth.
  • VISTA monotherapy failed to inhibit Treg recruitment into the TME.
  • Combination of anti-VISTA and anti-CTLA-4 elicited further tumor regression, suppressed Tregs, and improved CD8 T/Treg and CD4 Tcon/Treg ratios.
  • Combination of anti-VISTA and anti-PD-1 increased tumor-recruiting CD8+ T cells but decreased the Tcon/Treg ratio.

Conclusions:

  • VISTA blockade effectively converts CD8+ T cells into functional effector cells but is insufficient for tumor regression alone due to inadequate Treg suppression.
  • Combined CTLA-4 and VISTA blockade demonstrates superior efficacy compared to PD-1 and VISTA blockade in SCCVII models.
  • This combination strategy holds promise for head and neck squamous cell carcinoma and other tumors where Treg-mediated immune suppression is dominant.
Keywords:
CTLA-4Head and neck squamous cell carcinomaImmune checkpoint inhibitorImmunotherapyPD-1Tumor microenvironmentVISTA

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