Natural killer (NK) cells are lymphocytes, immune cells which have a powerful arsenal of cytotoxic weaponry that they can use against tumors.
Unfortunately, tumors protect themselves using a protective microenvironment that shields them from attack from NK cells. This microenvironment promotes tumor growth and survival and has an immunosuppressive effect that blunts the attempts of NK cells to infiltrate the tumor and destroy it. That was until now and this new discovery.
Infiltrating the tumor by blocking autophagy
A research team at the Luxembourg Institute of Health (LIH) led by Dr. Bassam Janji studied a highly aggressive form of skin cancer to reveal a mechanism by which this microenvironment could be switched. The new study shows that natural killer cells can be attracted to tumors to destroy cancer by switching the protective microenvironment with which the tumor shields itself from an immunosuppressive one to an immunosupportive one.
They discovered that if they blocked the intracellular garbage disposal process known as autophagy, it causes the tumor to produce cytokines (signals) that attract more NK cells to the location. This mass recruitment of NK cells all swarming to the tumor site allows for the destruction of cancerous cells and for the tumor to be reduced in size.
One of the hallmarks of cancerous, malignant tumors is evasion and suppression of the immune system. This happens due to the ability of tumors to create an immunosuppressive microenvironment that prevents cytotoxic immune cells, such as NK cells, from infiltrating tumors and killing the cancer cells. Thus, a key challenge in the field of immunotherapy for cancer is to develop therapies that can promote the infiltration of cytotoxic immune cells into the tumor bed.
It has been known for some time that the suppression of autophagy in cancer cells can help to reduce tumor growth. Inhibiting autophagy is known to make tumors more vulnerable to chemotherapy, but what was less understood was its impact on immune evasion.
Guiding NK cells to the tumor
The research team investigated the effect of inhibiting autophagy on the infiltration of NK cells in melanoma in this new study. The team discovered that they could block the autophagy process in tumor cells by inhibiting the expression of BECN1, an autophagy-associated gene found in mammals, including humans. When they did this, a large number of NK cells swarmed to the tumor and infiltrated it, bypassing the immunosuppressive microenvironment. This led to a significant reduction in tumor size.
The team showed that autophagy-blocked tumor cells produce more CCL5, a cytokine that attracts NK cells to the tumor bed. When CCL5 levels fall, the infiltration of NK cells and tumor regression is halted, thus confirming that CCL5 is critical in promoting the infiltration of NK cells into autophagy-defective tumors. Similarly, they discovered a positive correlation; the higher CCL5 levels are, the more tumors are infiltrated by NK cells.
The researchers also found that this increased production of CCL5 in autophagy-blocked cells was due to the activation of the kinase JNK and the transcription factor c-Jun. Additionally, a high level of CCL5 was also linked to the survival of melanoma patients.
This is the first time a mechanistic link between the autophagy process and NK cell recruitment has been established. The potential for targeting autophagy in tumor cells is a promising approach for helping the immune system to combat cancer. This could pave the way for developing NK cell-based immunotherapies, as we now know how to disable the immunosuppressive tumor environment.
The next step the researchers are taking is to test the impact of targeting autophagy blockades on other types of immune cells in the melanoma tumor environment. The ultimate goal is to provide a proof of concept for blockading autophagy to improve the efficacy of immunotherapies, most importantly those based on immune checkpoint blockades.
The field of immunotherapy is a rapidly advancing one and is something we are keeping a close eye on here. The defeat of cancer, a disease driven by DNA damage caused by aging or environmental stressors, is of great interest to us, as it relates directly to rejuvenation biotechnology.
When Nixon started his war on cancer in 1971, it is hard to think he could have imagined the idea of using our own immune system as a way to fight and defeat cancer, but many years later, here we are. Science is making huge progress in defeating cancer, and we sincerely hope the day comes soon when we can bring it under full medical control.
 Mgrditchian, T., Arakelian, T., Paggetti, J., Noman, M. Z., Viry, E., Moussay, E., … & Robert, C. (2017). Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner. Proceedings of the National Academy of Sciences, 114(44), E9271-E9279.