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There are growing evidences that tumor radiosensitivity is associated with immune activation in solid tumors. However, previous studies have not examined the relationship between patterns of immune infiltration and radiation response according to diverse molecular subtypes of breast cancer. This study evaluated radiosensitivity and immune infiltration signature to define a group of patients would benefit most from radiation therapy.  

We performed integrative analyses of the clinical, genomic, transcriptomic, and immunogenomic data to characterize the molecular features associated with radiosensitivity. We analyzed 1,903 data sets of METABRIC Study cohort using the radiosensitivity index (RSI), CIBERSORT and xCell, gene expression deconvolution algorithm which estimates the immune composition of tumor samples. According to RSI cut-point (0.3745), the patients were grouped into radiosensitive (RS, RSI-low tumors, n=1,082) versus radioresistant (RR, RSI-high tumors, n=821). Next, patients were divided into two groups according to immune and stromal scores, immune infiltrated (IF, n= 650) and immune excluded (IE, n=1253) subgroups. 

RS group showed improved prognosis compared to RR group, and IF group had better survival than IE group, however, these tendencies were only significant in ER-negative patients. Radiosensitivity was significantly associated with the activation of antitumor immunity. In contrast, radio-resistance was associated with metastatic properties, such as epithelial-mesenchymal transition and angiogenesis. Differentially expressed gene analysis revealed that ER signaling pathway is correlated with suppression of antitumor immunity. Higher ER was associated with a higher fraction of M2 macrophage and lower PD-1 expression. Integration of immune signature and radiosensitivity index further stratified patients into four subgroups. In ER-negative disease, IF and RS groups were associated with the best prognosis, whereas in ER-positive disease, immune signature and radiation response have no prognostic significance. On multivariable Cox regression, both integrated immune infiltration and radiosensitivity signature was independent predictors of relapse-free survival (HR 1.12, 95% CI 1.06-1.19, p < 0.001) and overall survival (HR 1.06, 95% CI 1.01-1.11, p = 0.028).

Taken together, this results suggested that tumor radiosensitivity was associated with activation of antitumor immunity and led to better prognosis particularly in ER negative group.