Effects of prior irradiation on the microenvironment of a radiation-associated breast cancer model increase sensitivity to immune checkpoint inhibition.

PURPOSE: Radiotherapy confers a later risk of secondary malignancies, including radiation-associated breast cancer. Distinctive molecular profiles emerge in tumors from pre-irradiated tumor beds, but effects on therapeutic options remain understudied.

METHODS AND MATERIALS: We developed a murine model of radiation-associated breast cancer by transplanting p53-mutant mammary HC11 epithelial cells that had been previously exposed to radiation (HC11RT) into mammary fat pads (MFP) that had been previously irradiated.

RESULTS

Tumor incidence from HC11RT cells increased two-fold when grown in irradiated MFP. Compared to tumors grown in sham-irradiated MFP, tumors from irradiated MFP had elevated TGFβ in both tumor and CD8+ T cells and elevated PD-L1 on CD4+ T cells, resulting in improved response to immune checkpoint inhibition (ICI).

CONCLUSIONS

This study provides evidence that prior irradiation potentiates tumorigenesis and immune evasion through both tumor cell autonomous and non-autonomous mechanisms. As a result, radiation-associated cancers may exhibit greater response to ICI than tumors of the same histology that are not associated with prior radiotherapy.