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. 2015 Jan 1;75(1):5-10.
doi: 10.1158/0008-5472.CAN-14-2538. Epub 2014 Dec 18.

Cancer Immunotherapy and Breaking Immune Tolerance: New Approaches to an Old Challenge

Free PMC article

Cancer Immunotherapy and Breaking Immune Tolerance: New Approaches to an Old Challenge

Amani Makkouk et al. Cancer Res. .
Free PMC article


Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor mAb and chimeric antigen receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor-specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T-cell activation. Recent advances in the use of checkpoint blockade to block negative signals and to maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested, and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of patients with cancer.


Figure 1
Figure 1. Immune tolerance and the antitumor immune response
Immune tolerance includes central tolerance (immune editing in the thymus) and peripheral tolerance (suppression of autoreactive lymphocytes in peripheral lymphoid tissue) (1). An effective antitumor immune response starts with tumor antigen release and uptake by DCs (2), antigen processing (3) and presentation by DCs in a stimulatory context to antigen-specific T cells (4), and the activation and proliferation of those T cells (5). The final step is the maintenance of the activated T cell response (6) to effectively eliminate the cancer in a tumor microenvironment rendered immunosuppressive by tumor cells and suppressive immune populations (MDSCs and Tregs). Immune tolerance can result from suppression at one or more of these steps. DC: dendritic cell; MHC: major histocompatibility complex; TCR: T cell receptor; MDSC: myeloid-derived suppressor cells; Treg: regulatory T cells.

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