The butterfly effect: Combinations of immunotherapy and radiotherapy to amplify the abscopal effect in metastatic disease.

Combination therapies are known to be effective in treating cancer, and there have been many advances with the use of two or more therapies that have either an additive or a synergistic effect upon treating disease. Often, the use of a combination therapeutic will reduce the overall toxic effects of chemotherapeutics on healthy tissue, which has a huge clinical benefit. A lot of combination therapies are used in conjunction with chemotherapy, but there are also combination therapies that are being researched that can positively impact the “abscopal effect” of radiotherapy.

A recent article in Nature Reviews Cancer has outlined the developments in research that have provided evidence that the abscopal effect can be boosted with a combination of radiotherapy and immunotherapy1.

The abscopal effect (from the Latin for “away from target”, ab scopus), was first described in a paper in 1953 in which metastatic cancer sites were found to regress away from the site where radiotherapy was administered2.  This beneficial off-target impact is known to be driven by the immune system, but is a rare event because in the tumour microenvironment, weakened immune responses may restrict the development of an abscopal response. However, there is growing evidence to support the idea that using a combination of radiotherapy and immunotherapy may boost the abscopal effect.

Whilst the exact mechanism of the abscopal response is not completely understood, there are multiple studies that have highlighted how combining an immunotherapeutic with radiotherapy can boost its effect. Upon injury through radiation, a tumour can release tumour-specific antigens, which are presented by antigen-presenting cells to CD8+ T cells. These T-cells can then identify both the tumour that has been irradiated and also areas of metastatic disease to be targeted for attack by the adaptive immune system3 (Fig. 1). Damage-associated molecular patterns (DAMPs) and cytokines may also be expressed by the irradiated tumour cells to further feed into the inflammatory cascade that leads to the ultimate cellular elimination by CD8+ T-cells 4.

Will Pearce 1

Fig.1 The inflammatory cascade involved in the abscopal effect1

However, the rarity of the abscopal effect suggests that the immunosuppressive microenvironment of tumours inhibits the ability of primed CD8+ T-cells to identify tumour cells and target them for elimination. This is possibly due to immunosuppressive cytokines such as TGF-β and surface receptors such as CTLA4, which can inhibit T-cell function4. Therefore, methods to overcome the immunosuppressive microenvironment of tumours have been explored to assess whether overcoming immunosuppression by inhibiting Treg cells using anti-CTLA4 and PDL-1  (programmed cell death protein 1) blockade can lead to increased CD8+ T-cells:Treg cell ratios. In theory, this would make the tumours more sensitive to CD8+ T-cells and lead to adaptive immune responses aimed at the tumour and metastases, which would boost abscopal responses.

Other methods of overcoming immunotherapy include direct injection of IL-2 (a proinflammatory cytokine) or dendritic cells (DC) into the irradiated tumour. Boosting DC numbers in the irradiated tumour will lead to an increase in tumour-specific antigen presentation and therefore a larger adaptive immune response. Injection with IL-2 leads to inflammation and therefore a boost in the abscopal effect. All of these methods are aimed at overcoming immunosuppression and therefore better targeting of the tumour and metastases by the immune system.

There are many examples in which combinations of radiotherapy and immunotherapy could be used to boost abscopal effects and therefore treat metastatic disease, which is known to account for most of the fatality associated with cancer. It is therefore an important area of research and an interesting approach to combination therapy in cancer.

Blog written by Will Pearce

  1. Ngwa, Wilfred et al., Nat. Rev. Cancer., 2018, Vol.18., 313-322
  2. Mole, R.H., BR J Radiol., 1953, Vol.26, 234-241
  3. Grass, G.D. et al., Curr. Probl. Cancer., 2016, Vol. 40., 10-24
  4. Vatner, R.E., et al., Front Oncol., 2014, Vol. 4., 325



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