The abscopal effect refers to the ability of localized radiation treatment of a tumor to have systemic anti-tumor effects.
In the past, this has been rare and deemed almost a magical form of recovery. However, with continued developments in cancer research and immunotherapy strategies, this miraculous form of recovery is becoming more of a realistic possibility for cancer patients.
How does this work exactly? Formerly, radiation therapy has been used as a localized treatment focused on controlling and killing cancer tumor cells by direct damage while minimizing healthy tissue damage. But as doctors are discovering, radiation therapy can elicit systemic tumor effects by acting as an immunomodulator to the tumor microenvironment.
Radiation can act as an immunomodulator in several ways. By inducing cell death, radiation causes a release of immunologic factors, one of these factors is improved antigen presentation to T cells. Radiation also causes local inflammation, which alerts the immune system. The immune system will send cells, including T cells, to the site of inflammation where they are presented with these antigens.
The antigens will then trigger the production of new antibodies that recognize the cancer cells as foreign. This is very important because one of the reasons cancer is so hard to kill is that your body doesn’t recognize it as foreign and therefore won’t attack. Now, after radiation, these new antibodies are traveling through the body and when they come across other cancerous tumors they know to attack.
However, it’s not perfect and there are also negatives to radiation therapy.
For example, it promotes certain cell types that fuel cancer growth. Not at the same speed as it kills cancer cells, but radiation can potentially promote:
- TGF-b (transforming growth factor-beta) a cytokine that is the protein used for signaling cell growth, proliferation, differentiation, and apoptosis. We certainly don’t want to promote these cytokines in areas with high levels of cancer cells.
- MDSC (myeloid-derived suppressor cells) a type of immune cell used to regulate functions of certain immune cells like T cells, dendritic cells, macrophages, and natural killer cells. Cancer tissue with increased MDSC are more resistant to therapies and usually have a worse prognosis.
- Regulatory T cells are a subpopulation of T cells that are immunosuppressive which is good in normal tissue to help maintain tolerance to self-antigens and prevent autoimmune disorders. However, we don’t want to promote any immunosuppressive agent in areas of cancer growth.
So this means that in order to achieve the abscopal effect, doctors are using other immunotherapy agents in combination with radiation therapy to help combat these negative potential results. By using radiation therapy combined with immunotherapy, doctors believe the abscopal effect will be much more attainable.
Immunotherapy, in this case, refers to targeted immunomodulatory drugs for example (generic names) Yervoy, Keytruda, Opdivo, Tecentriq, Bavencio, or Imfinzi may be given to patients undergoing radiation therapy. These drugs act mostly as checkpoint inhibitors. Checkpoint inhibitors block the normal proteins on cancer cells. When these proteins are blocked, the cancer cells can no longer hide from the immune system and will instead be attacked by T cells.
When radiation therapy is combined with immunotherapy we really start to see the ideal abscopal effect take place.
The combination therapies not only work together to block checkpoint proteins but also enhance other immunostimulatory signals. Certain immunostimulatory molecules that are released include:
- Cytokines in the form of growth factors for dendritic cells. Dendritic cells act as messengers for the immune system by presenting it with antigens.
- Cytokines in the form of chemokines which help to recruit immune cells to a site of infection or in this case inflammation.
- Increased PD-L1 (programmed death-ligand 1) which helps to induce apoptosis and in this case can synergistically work with radiation to reduce MDSCs.
The science is not yet perfected, and everyone is different. There are so many variables to consider including what type of cancer a patient has and how their specific immune system will respond to treatments. It is important to define optimal radiation dosage, timing, and type of immunotherapy drug. Each case will be slightly different and what works for someone may not work for another. With that being said the research is very promising and can hopefully shed some light on future cancer treatments.