Hypofractionated radiotherapy and tumor immunity — new concepts and new combination

Modem immunology has established that tumor immune escape is associated with hidden or missing tumor-specific antigens and tumor-associated antigens, as well as immune suppressors that are released from tumor cells to inhibit the immune cytotoxicity and antigen-presenting cells (APCs). The changes in tumor microenvironment have an impact on tumor immunity and treatment outcomes. The immune effects finally depend on activation and inhibition of T cell receptors and other co-regulated receptors (CD₂₈, CD₈₀/CD₈₆, and CTLA-4) in spite of the existence of APCs and cytotoxic T lymphocytes in tumor microenvironment. Recent studies have revealed that radiotherapy induced not only DNA damage but also immunogenesis in tumor cells. Both conventionally fractionated radiotherapy and hypofractionated radiotherapy can induce immunogenesis in tumor cells. Immunogenic regulation makes many tumor antigens expressed in cells exposed to irradiation, which induces immune recognition and cytotoxicity; cell content (DNA, HMGB1, etc.) released from dead immunogenic cells can trigger immune effects and in situ tumor vaccination, which further induce an abscopal effect of radiotherapy. A lot of anti-tumor immunotherapy fails to achieve satisfactory treatment outcomes. Therefore, how to combine radiotherapy, especially stereotactic body radiotherapy, with anti-tumor immunotherapy has recently become a new challenge for researchers. (authors)