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Future directions in tumor immunotherapy: CTLA4 blockade

Nature Clinical Practice Oncology volume 4, pages 136–137 (2007)Cite this article

The human immune system can identify and react to an immense array of targets. Strong regulatory mechanisms that protect against autoimmunity prevent undesirable immune responses to self-antigens. Unfortunately, since many tumor-associated antigens (TAA) are merely self-antigens that are differentially overexpressed in tumors, these same regulatory mechanisms may prevent tumor-specific immunity sufficient for clinical activity. In addition, inhibitory immune regulation may limit clinically significant antitumor immune responses because chronic antigen stimulation can trigger anergy of tumor-specific T cells. Over the last decade, cytotoxic T-lymphocyte associated molecule 4 (CTLA4) has emerged as a key mediator of immune response attenuation.1

For most weak antigens (e.g. TAA), a signal from the T-cell receptor is insufficient to optimally activate the T cell.2 A second immune-enhancing signal is required to activate the T cell specific for the target antigen. This signal is generated when CD28 on the T cell binds to B7 on the antigen-presenting cell. CTLA4 becomes expressed on the surface of the T cell within 2–3 days following activation and also binds to B7. The higher-affinity binding of CTLA4 to B7 generates a negative signal, effectively halting an ongoing immune response. The key regulatory role of CTLA4 is underscored in CTLA4 knockout mice that cannot turn off immune responses and live only 2–3 weeks before succumbing to massive infiltration of organs by unchecked growth of autoreactive T cells.3 Thus, antagonistic antibodies that prevent CTLA4 signaling may enhance T-cell expansion.

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Authors and Affiliations

  1. JL Gulley is Director of the Clinical Immunotherapy Group at the Laboratory of Tumor Immunology and Biology, and WL Dahut is Chief of the GU/GYN Clinical Research Section in the Medical Oncology Branch, the National Cancer Institute, Bethesda, MD, USA.,

    James L Gulley & William L Dahut

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  1. James L Gulley
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  2. William L Dahut
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Correspondence to William L Dahut.

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The authors declare no competing financial interests.

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Gulley, J., Dahut, W. Future directions in tumor immunotherapy: CTLA4 blockade. Nat Rev Clin Oncol 4, 136–137 (2007). https://doi.org/10.1038/ncponc0749

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