Cancer Immunotherapy - A Dramatic Advancement towards Gentle Cancer Treatment

Figure 1. Cancer immunotherapies developed in the last three decades. Image from Galluzzi et al. 2014.
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Figure 2. Immunohistochemical staining (brown) of PD-1 and PD-L1 in germinal centers of tonsils and PD-L1 in urothelial cancer tissue.

The 2018 Nobel Prize in Physiology or Medicine, awarded jointly to Dr. James P. Allison and Dr. Tasuku Honjo for their contribution to cancer immunotherapy, highlighted the dramatic advancement of our understanding of cancer immunology in recent decades. Previously untreatable groups of cancer patients are now given a chance to prolong their lives.

In recent decades, the mechanisms and pathways underlying the immune system's response towards cancer cells have been extensively elucidated. We now know that our immune system protects us against cancer throughout our lives. The cells of the immune system identify and clear malignant cells that either express abnormal proteins, so called tumor-associated antigens (TAAs), or lack certain cell surface proteins. However, cancer cells are sometimes able to evade the immune system and at that point it becomes necessary to treat the cancer. Until recently, treatment options mainly included surgery, radiation and chemotherapy. These damaging treatment options are now being challenged by relatively benign manipulations of the immune system.

Cancer immunotherapy encompasses an ever growing list of different approaches to either initiate an anti-cancer immune response or enhance an existing immune response against cancer cells (Figure 1). Immune checkpoint blockade, the approach based on Dr. Allison and Dr. Honjo's work, involves enhancing the anti-cancer immune response of cancer patients by inhibiting the natural immunosuppressive function of the immune system. Such inhibition is facilitated through the use of antibodies that bind and block the signal of two different immunosuppressive receptors, CTLA-4 and PD-1. Both are expressed on the cell surface of T-cells and play a vital role in preventing the immune system from attacking healthy cells. In the germinal centers of secondary lymphoid tissue, where adaptive immune responses are initiated, T-cell PD-1 and its ligand PD-L1, expressed on B-cells and antigen presenting cells, interact to suppress autoimmune responses (Figure 2). PD-L1 has also been found to be expressed in cancer tissue to suppress the anti-cancer immune response (Figure 2). As a result, the PD-1 signal pathway has emerged to serve as a cancer immunotherapy target, blocked with PD-1 or PD-L1 specific antibodies, a treatment that currently saves the lives of previously untreatable cancer patients.

Even though immunotherapy has advanced the field of cancer treatment, only a minority of patients respond to immunotherapy treatment. Cancer heterogeneity, the cancer cell's ability to develop resistance to immunotherapies, and ineffective treatment strategies are some of the main reasons behind the lack of patient responsiveness. Current efforts to overcome these challenges include more research in the area to generate increasingly personalized treatment strategies using optimized combinations of immunotherapies.

Expression patterns of known and candidate cancer immunology associated genes can be explored on mRNA and protein level in a large collection of human normal and cancer tissues at Tissue Atlas and Pathology Atlas, respectively.

Andreas Digre