Can Our Immune System be Directed to Kill Cancer Cells? Limitations and Solutions

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Hema Saranya Ilamathi

Beep! Beep! There goes the metal scanner in the airport. Oops! I realized that I forgot to take out the key chain from my pocket. Similar to the metal detection system, our body has a highly vigilant surveillance system called immune cells that constantly scan for the presence of foreign molecules in the body. Moreover, they actively monitor for abnormalities in the body cells and help to eliminate aberrant cells including cancer cells. 

Based on this natural phenomenon, various immunotherapeutic strategies are developed against cancer that is either approved by FDA or in clinical trials. These immunotherapeutic treatments either activate antitumor response or override immunosuppressive effects of cancer cells, with some of them showing encouraging results (https://www.nature.com/articles/s41422-020-0337-2/tables/1). Among them, antibodies that block CTLA4 (cytotoxic T lymphocyte-associated protein 4) and PD1 (programmed cell death protein 1) show promising results and are approved for cancer therapy. In addition to antibodies, cell-based therapy is another prospective approach to treating cancer. In this therapy, the patient’s immune cells are isolated, genetically modified to target cancer cells, and injected back into the patient. This increases the repertoire of arsenal targeting cancer cells. For instance, five chimeric antigen receptor (CAR) T-cell therapy has been approved by the FDA to treat lymphoma and myeloma, cancer that affects blood cells.

Although immunotherapy is one of the effective ways to treat cancer, there are a few challenges associated with it. Cancer cells actively re-orchestrate their tumor microenvironment to make it unfavorable for the immune response. Generally, cancer cells manipulate the microenvironment in the following four ways: 1) deplete nutrients from the microenvironment necessary for proper immune cell function, 2) acidify the microenvironment and make it unfavorable for immune cell function, 3) trick the immune system cells by disguising as “normal cells” and, 4) by inducing an immunosuppressive environment by attracting other immune cells that can suppress the antitumor effect. These immunosuppressive effects of cancer cells limit the success of immunotherapy in patients.

In addition to these challenges, using a single immunotherapeutic approach results in the development of resistance in cancer cells. Immunotherapeutic antibodies and immune cell-based therapies are developed based on the surface proteins expressed in the cancer cells. However, when a single surface protein is targeted, cancer cells compromise immune response by decreasing the expression of the targeted protein on their surface. Combination therapy could help to overcome the complications associated with monotherapy. In this therapeutic approach, multiple cell surface proteins could be targeted to kill cancer cells. Furthermore, combining immunotherapy with traditional therapy such as chemotherapy and radiotherapy shows positive outcomes in clinical trials.

Besides these limitations, the success rate of immunotherapy is also highly influenced by the targeted cancer cell surface protein. Some patients have cancer cells that highly express targeted surface protein (‘hot tumor’) resulting in a successful immunotherapy outcome. On the other hand, some patients have cancer cells that are less likely to express the targeted surface protein (‘cold tumors’) resulting in a poor therapeutic response. Hence, personalized immunotherapy approaches are essential to overcome the variability in the treatment results. Furthermore, regular follow-up on the tumor and its microenvironment during immunotherapy can help to tailor the treatment regime and avoid tumor resistance. 

Immunotherapeutic strategies are being developed based on the body’s natural defense system. However, immunotherapy can activate an autoimmune response in some patients where immune cells target normal cells. These undesirable side effects can be eliminated by selecting markers specifically localized to tumors. In addition, regular monitoring of the immunotherapeutic response in patients and modulation of the immunotherapy dosage can help to avoid the undesirable side effects associated with it.

Although there are a few limitations, immunotherapy still holds a promising approach to treating cancer. Further research and optimization are required to harness the potential of immunotherapy. Among them, 1) identifying cancer-specific surface proteins for immunotherapy, 2) targeting multiple surface proteins at the same time, 3) optimizing the time and dose of immunotherapeutics, and 4) regular monitoring of treatment outcome will increase the success rate of the treatment. Furthermore, developing a quick and cost-effective way to examine cancer cells in patients can help to develop personalized immunotherapy regimens and avoid variability in treatment outcomes. However, targeting only immune cells could compromise treatment efficiency as cancer cells are highly adaptive to favor their growth and survival. For example, cancer cells utilize metabolites such as glucose, amino acids, and lipids and deprive immune cells of essential nutrients for their survival and function. In addition, cancer cells develop an acidic environment around themselves which favors the immunosuppressive cells and blocks the action of antitumor-modulating immune cells. Hence, a treatment regime that involves targeting cancer cells and modulating antitumor immune response could be an alternative approach to combat cancer.

Edited by Ifeoluwa Oyelade

Reference

1. Yu Y, Cui J. Present and future of cancer immunotherapy: A tumor microenvironmental perspective. Oncol Lett. 2018 Oct;16(4):4105-4113. doi: 10.3892/ol.2018.9219. Epub 2018 Jul 26. 
2. Murciano-Goroff, Y.R., Warner, A.B. & Wolchok, J.D. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res 30, 507–519 (2020). https://doi.org/10.1038/s41422-020-0337-2
3. Ventola CL. Cancer Immunotherapy, Part 3: Challenges and Future Trends. P T. 2017 Aug;42(8):514-521.