How do cancer cells that only absorb a sublethal dose of radiation get destroyed by the immune system?

In a recent article on combined radiation and immune therapy, I made the following statement without further explanation: “Radiation-modified cancer cells that escaped direct annihilation become more immune-susceptible too.” This effect is known as “immune modulation” and has previously been observed in test tube and mouse studies in castrate-resistant prostate cancer cells. A new study by Gameiro et al. of NCI/NIH extends the observation to the kind of cells responsible for hormone-sensitive bone metastases, and provides a biochemical mechanism for the observed effect. Because radiation alone only results in weak immune modulation, it is hoped that by understanding the precise mechanism responsible for radiation-induced killing of cancer cells by cytotoxic T cells, called “immunogenic cell death”, we can tailor therapies given along with radiation to enhance and sustain the immune modulation effect.

The precise mechanism is very complex. The radiation causes stress on internal components of the cancer cell. In an effort to recover, the cell activates its antigen-presenting machinery, and a protein called calreticulin moves to the cell surface where it attracts cytotoxic T cells.

This study provides a rationale for the use of immunotherapy to enhance the cancer cell killing of radiation alone. It also identifies stages in the process that can potentially be inhibited or enhanced by biochemicals and other molecules. Clinical trials will determine which immune enhancements are most effective.

This study was conducted by the National Cancer Institute of NIH. It is the kind of painstaking basic medical research that is critical to the development of new and improved therapies, and the kind that private companies and even universities are often reluctant to undertake because the rewards, if any, are so far in the future.

As a side note, it's worth mentioning that adjuvant ADT and radiation seem to work synergistically to enhance the immune effect. One can read about evidence of the combined effect of ADT and immunotherapy in a recent review by Antonarakis and Drake. One of the open questions is the optimal timing of all three therapies. In one mouse study, the authors conclude: “These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.” However, another mouse study draws the opposite conclusion: “androgen ablation improved immune responses to vaccination only when applied after immunization.” They are only mouse studies, so it’s difficult to draw conclusions about humans, but they illustrate that there is much still to be learned about all this.