Cancer-Immunity Cycle

The cancer-immunity cycle is a process initiated by the release of cancer cell antigens that concludes with the destruction of cancer cells. Daniel S. Chen, MD, PhD, and Ira Mellman, PhD, detail the steps of the cancer-immunity cycle in a manuscript published in the journal Cell Press in 2013. A summary of the steps described by Chen and Mellman is found below.

Cancer-Immunity Cycle

Source: Chen DS, Mellman I. Immunity. 2013;doi:10.1016/j.immuni.2013.07.012.

Step 1 – Neoantigens are released by tumors as they die off and are captured by the antigen-presenting dendritic cells, which process the antigens to produce peptides that bind to major histocompatibility complex (MHC).

Step 2 – Peptides bound to MHC-I and MHC-II molecules are presented to T cells. CD4⁺ T cell receptors can recognize the peptide-MHC-II molecules.

Step 3 – Effector T cells are primed and activated to respond to the tumor antigens presented. Three classes of antigens with high tumor specificity may be identified by T cells: antigens produced from mutated cells, cancer-germline genes and viral genes.

Step 4 – Activated T cells move to the tumor site and infiltrate the tumor.

Step 5 – Activated T cells bind to cancer cells. T cells are able to recognize cancer cells as foreign based on the antigens they released earlier, specifically binding to cancer cells through the interaction between the T-cell receptor and its cognate antigen bound to MHC-I on the surface of the cancer cells.

Step 6 – Activated T cells kill cancer cells. T cells eliminate cancer cells by activating a series of steps that lead to cell death. The dying cancer cell releases additional cancer-specific neoantigens (Step 1) to continue the cycle and amplify the anticancer response.

As the cycle continues, more and more tumor antigens are released during cell death, thereby strengthening the immune response of the T lymphocytes. Stimulatory factors promote immunity, whereas inhibitory checkpoint proteins, such as CTLA-4 and PD-L1, work at different steps of the cycle to reduce immune activity and, in this manner, also prevent autoimmune responses. A central goal of immunotherapy is to trigger the cancer-immunity cycle without harming normal cells; thus, many immunotherapeutic agents target steps in the cancer-immunity cycle.

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