CTLA-4 expression by human tumor cells and its impact on immunotherapeutic strategies: a systematic review

Published: 23 June 2021
Review
Farah Abdulkhaleq,
Farah Abdulkhaleq
Equally contributing first author Institute of Medical Sciences, University of Aberdeen, UK
Niss Larossi,
Niss Larossi
Equally contributing first author Institute of Medical Sciences, University of Aberdeen, UK and Institute of Biological Sciences, University of Manchester, UK
Okanda Ogbonda,
Okanda Ogbonda
Equally contributing first author Institute of Medical Sciences, University of Aberdeen, UK
Rasha Abu-Eid,
Rasha Abu-Eid
Co-corresponding author Institute of Medical Sciences, University of Aberdeen, UK and Institute of Dentistry, University of Aberdeen, UK rasha.abueid@abdn.ac.uk
Frank James Ward
Frank James Ward
Co-corresponding author Institute of Medical Sciences, University of Aberdeen, UK mmd475@abdn.ac.uk

Background: Cancer is a leading cause of death worldwide and its development is closely related to immune dysfunction. Immune checkpoint (IC) receptors maintain immune homeostasis to protect normal tissues, but cancers use several immune escape mechanisms including altered IC expression to evade destruction by the immune system. Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is one such IC, which downregulates T-cell activation. There are at least two isoforms of CTLA-4 in humans; the full-length receptor isoform and an alternatively spliced soluble CTLA-4 (sCTLA-4) isoform. The aim of this systematic review is to investigate whether or not human tumor cells express CTLA-4, and to examine if there are any consistent retrospective correlates of increased CTLA-4 expression with disease outcome.

Methods: We searched Medline, Scopus, Embase and Web of science for original research articles that investigated CTLA-4 expression by human primary tumor cells or tumor cell lines, from 1987 to April 2020. Forty-five records were deemed eligible and data describing tumor site and stage, CTLA-4 isoform studied, test sample and control groups involved, methods and level (mRNA or protein) of detection, location and any retrospective association with disease outcome were extracted.

Results: Of the forty-five eligible manuscripts, thirty-eight studies focused on the full-length isoform, one study focused on the soluble isoform and six studies investigated both. Forty-two studies reported an increase in CTLA-4 detection by cancer cells. Twenty-one manuscripts performed a retrospective comparison of patient outcomes in CTLA-4 high and low groups in terms of overall survival; eleven studies found that high tumor CTLA-4 expression correlated with poor outcome while seven studies found an opposite correlation. Three studies, however, reported no association.

Conclusions: This review provides strong evidence that a variety of cancer cells express both CTLA-4 transcripts and functional CTLA-4, detectable in the cytoplasm or on the cell surface. Overall, the data suggest that CTLA-4 expression levels in cancer cells are an important but variable feature of the disease phenotype, which will be both increasingly important to evaluate in the context of immune CI therapeutics, and may also be a useful response biomarker.

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