We often hear about how the immune system is harmed by conventional treatments such as high-dose chemotherapy and radiotherapy. But few people realize that low-dose versions of these same treatments can actually stimulate the immune system, and radiotherapy has been shown to trigger certain immune mechanisms that can help combat cancer. Trouble is, these treatments still have toxic side effects. And because low doses can’t directly eliminate the primary tumor, such doses are rarely used.
The light-based approach called photodynamic therapy, or PDT, is free of any of these problems, and it has a far more favorable impact on anti-cancer immunity. PDT is non-toxic and can accomplish both goals at once, not only removing the primary tumor but also activating the immune system so as to clear away residual cancer cells as well as metastases located far from the tumor. (To achieve the latter effect, however, additional immune support is often needed, as reported in previous Discoveries articles.)
Because of these beneficial immune-related effects, PDT is classified as an immunogenic therapy, along with hyperthermia (the use of heat) and a few other treatment modalities. When we say PDT can kill cancer cells in an immunogenic manner, we mean that it stimulates the immune sytem in specific ways that are conducive to the elimination of those malignant cells. In essence, it causes the death of cancer cells in ways that “excite” or turn on the immune system. This is technically known as immunogenic cell death.
When PDT destroys tumors, two groups of signals are released by the disease itself. The first group is the tumor antigens, proteins that are are part of the tumor. The second group of signals are the alarm or danger signals. These are the more critical group of signals, because without them the immune system does not recognize the cancer as a threat. This second group of signals is technically referred to as damage-associated molecular patterns or DAMPs.
Understanding the Significance of DAMPs
So what exactly are DAMPs? These are molecules released from the tumor as the tumor becomes stressed or damaged, as in the case of PDT. The molecules are normally confined within the living cell in parts or “compartments” such as the nucleus or in biological membranes. As DAMPs are secreted by the damaged and dying cells, they tend to acquire the ability to stimulate the immune system.
Three major DAMPs, have been identified, and they go by some fairly technical-sounding names: calreticulin, heat shock proteins 70, and high mobility group box 1. The combination of these three major DAMPs has been linked with the immunogenic cell death phenomenon described above.
On a more practical level, the signals released by PDT (both antigens and DAMPs) can be used to generate an anticancer vaccine that is specific for the patient. It turns out that DAMPs have the ability to activate immune cells like macrophages, certain T cells, NK cells, and dendritic cells—all of which participate collectively in the eradication of cancer, including metastases.
Science Proves PDT’s Impact on Cancer-Killing Immunity
So how exactly does PDT influence the immune system to better eradicate cancer? This question was the focus of a recent study conducted by scientists based in China and the United States. The US scientists were from the Biophotonics Research Laboratory at the University of Central Oklahoma in Edmond, Oklahoma (USA). The Chinese researchers were based at the Shanghai Skin Disease Hospital and Fudan University’s Huadong Hospital, both in Shanghai, China.
In a previous study, the USA-China team had observed that PDT-treated tumor cells could trigger the maturation of key immune cells called dendritic cells, essentially making these cells more capable of signaling the T-cell system to attack cancer. Those findings indicated that PDT can be highly effective in enhancing the immune system’s ability to recognize tumor cells.
In a more recent study, the USA-China team investigated the effect of PDT-induced DAMPs on various groups of immune cells. Following PDT treatment of tumor-bearing mice, they observed increased expressions of DAMPs. They found that PDT generated all three major groups of DAMPs mentioned above. These DAMPs, in turn, were linked with the increased maturation of dendritic cells needed to activate the immune system against the cancer, as reported online ahead-of-print in the 26 November 2015 issue of Oncotarget.
Again, this research shows that PDT is not only capable of directly destroying tumors, but that it also transforms the dying cancer cells into major generators of signals that “wake up” the immune system—signals that generate a specific immune response against residual cancer cells and potentially deadly metastases. This unique ability of PDT to activate the immune system is attracting the attention of cancer immunologists worldwide.
Similar support for this perspective comes from a study conducted at the East China University of Science and Technolog in Shanghai, China. The scientists reported that PDT had specific effects on a structure inside cancer cells that generates an imbalance between “eat me” and “don’t eat me” signals. This imbalance appeared to cause the aforementioned dendritic cells to “eat” or take up lung tumor cells that had been killed by PDT. The study’s findings points to “the possibility for developing PDT into an antitumor vaccination strategy for personalized cancer immunotherapy,” as reported in the January 2016 International Journal of Biological Sciences.
Zheng Y, Yin G, Le V, Zhang A, Chen S, Liang X, Liu J. Photodynamic-therapy Activates Immune Response by disrupting Immunity Homeostasis of Tumor Cells, which Generates Vaccine for Cancer Therapy. Int J Biol Sci. 2016 Jan 1;12(1):120-32.
Wang X, Ji J, Zhang H, Fan Z, Zhang L, Shi L, Zhou F, Chen WR, Wang H, Wang X. Stimulation of dendritic cells by DAMPs in ALA-PDT treated SCC tumor cells. Oncotarget. 2015 Nov 26. [Epub ahead of print]
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