Targeting the CTLA-4/B7 axes in glioblastoma: preclinical evidence and clinical interventions

ABSTRACT

Introduction

Glioblastoma Multiforme (GBM) is one of the fatal cancers of the Central Nervous System (CNS). A variety of reasons exist for why previous immunotherapy strategies, especially Immune Checkpoint Blockers (ICBs), did not work in treating GBM patients. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint receptor. Its overexpression in cancer and immune cells causes tumor cell progression. CTLA-4 suppresses anti-tumor responses inside the GBM tumor-immune microenvironment.

Areas covered

It has been attempted to explain the immunobiology of CTLA-4 as well as its interaction with different immune cells and cancer cells that lead to GBM progression. Additionally, CTLA-4 targeting studies have been reviewed and CTLA-4 combination therapy, as a promising therapeutic target and strategy for GBM immunotherapy, is recommended.

Expert opinion

CTLA-4 could be a possible supplement for future cancer immunotherapies of GBM. However, many challenges remain such as the high toxicity of CTLA-4 blockers, and the unresponsiveness of most patients to immunotherapy. For the future clinical success of CTLA-4 blocker therapy, combination approaches with other targeted treatments would be a potentially effective strategy. Going forward, predictive biomarkers can be used to reduce trial timelines and increase the chance of success.

KEYWORDS:

• CTLA-4
• immune checkpoint blockade
• glioblastoma
• cancer immunotherapy
• tumor microenvironment

Article highlights

• CTLA-4 is overexpressed in both glioblastoma and immune cells

• CTLA-4 overexpression inhibits anti-tumor responses

• CTLA-4 upregulation causes one of the worst pathogenic conditions in glioblastoma

• Higher sCTLA-4 levels lead to less survival time in glioblastoma

• The evaluation of CTLA-4 levels in serum and inside the tumor microenvironment could be a valuable biomarker for the better management of glioblastoma patients

• CTLA-4 blockade combination therapies could exert ameliorative effects on glioblastoma patients

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by Tabriz University of Medical Sciences (grant numbers: 68136 and 68137).