Development of the rationale of a personalized cancer vaccine based on the in situ vaccine effect of radiotherapy: a mechanistic study of the POLARSTAR trial.

PURPOSE: Radiotherapy induces multiple forms of tumor cell death, including immunogenic cell death (ICD) like GSDME-mediated pyroptosis and MLKL-mediated necroptosis; and ICD has been increasingly accepted as a crucial element leading to enhanced anti-tumor adaptive immunity. We aim to clarify whether a vaccine-like effect is intrinsic for radiation-induced tumor cell death, and to explore potential applications. METHODS: A randomized controlled trial was performed to validate the synergism between clinical radiotherapy and PD1 blockade in patients with resectable rectal cancer. Colorectal cancer cell lines and patient-derived organoids were used to study the impact of ionizing radiation on tumor cells. Syngeneic mouse tumor models were used to study the microenvironment modulating effect of localized irradiation, as well as the potential vaccine-like effect of the in vitro irradiated autologous tumor cells. RESULTS: For patients with locally advanced rectal cancer, adding immune checkpoint blockade to radiotherapy significantly increases tumor response rate. On cellular level, ionizing radiation induces GSDMD-mediated pyroptosis of colorectal cancer cells and increased the infiltration of cytotoxic T cells into tumor microenvironment. On syngeneic, immune-competent mouse tumor models, autologous tumor cells irradiated in vitro at a sterilization dosage work as a therapeutical vaccine to inhibit the growth of inoculated tumors. CONCLUSIONS: Radiation-elicited tumor cell death exhibited an in situ vaccine effect to potentiate immune checkpoint blockade, and autologous tumor cells irradiated in vitro at a sterilization level may serve as a candidate source of immunogen for personalized therapeutical cancer vaccine.