Cancer Immunotherapy
Tumour cells and cancer cells have many attributes that make them excellent survivors. For instance, tumours have adapted several mechanisms to evade or suppress the host's immune system, including secreting immunosuppressive cytokines such as transforming growth factor beta (TGF-β) and interleukin-10 or by deactivating T cells. This makes tumour cells resistant to elimination by the immune system (1). One mechanism employed by tumours that is of particular therapeutic interest is the exploitation of 'immune checkpoints'.
Figure 1: Murphy K, Travers P, Walport M, Janeway C. Janeway's immunobiology. New York: Garland Science; 2008.
Immune Checkpoints
Immune checkpoints are immunoregulatory molecules that either upregulate or downregulate a signal. Tumours have exploited molecules that do the latter in order to inhibit signals for killing tumour cells. These molecules generally decrease effector responses of T cells, B cells and NK cells, and increase responses of regulatory T cells (2).
Examples of functionally related inhibitory checkpoint molecules:
Cytotoxic T-lymhocyte associated protein 4 (CTLA-4) - present on the surface of T helper cells and engages with CD80/86 to inhibit co-stimulation.
Programmed cell death protein 1 (PD-1)
Lymphocyte activation gene 3 (LAG3)
These proteins are mainly present on the surface of immune cells. They act by downregulating effector T cell responses and enhancing regulatory T (Treg) cell responses (3). Some cancers increase the expression of ligands to these molecules creating an immunosuppressive microenvironment. Checkpoint expression may be increased during immune activation as part of a negative feedback loop to avoid autoimmunity. Both of these situations arise due to chronic antigen exposure (4).
Therefore, despite aiding cancer survival, these checkpoints are important for limiting autoreactivity. This is an important factor when considering immune checkpoint blockade therapies. The likelihood and benefit of successful treatment should outweigh the relative likelihood and damage of autoimmunity.
References
1. Sciencedirect.com. Hallmarks of Cancer: The Next Generation [Internet]. 2015 [cited 30 November 2015]. Available from:
http://www.sciencedirect.com/science/article/pii/S0092867411001279
2. Sharma P, Allison J. Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential. Cell. 2015;161(2):205-214.
3. Sojka D, Hughson A, Fowell D. CTLA-4 is required by CD4+; CD25+; Treg to control CD4+; T cell lymphopenia-induced proliferation. European Journal of Immunology. 2009;39(6):1544-1551.
4. Carter L, Fouser L, Jussif J, Fitz L, Deng B, Wood C et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. European Journal of Immunology. 2002;32(3):634.