The immune system plays an important role in the breast during normal, physiological changes as e.g., development, lactation and involution, but also during carcinogenesis. It is well-established that immunogenic cell death (ICD) induced by radiotherapy (RT) activates and attracts immune cells to the tumorarea. Recently, growing evidence from pre-clinical and clinical studies also show that presence of immune cells in the untreated tumor influences this immunogenic effect and affects the benefit from RT.
The normal breast contains a variety of different immune cells maintaining epithelial integrity via protection against endogenous and exogeneous pathogens (e.g., bacteria), but also through elimination of transformed cells. The majority of immune cells in the normal breast gland represents dendritic cells and cytotoxic (CD8+) T-lymphocytes, where the latter has been found to encompass mostly memory cells already activated by antigens. This indicates a high level of immune surveillance in the normal mammary gland with antigen-presenting and cytotoxic/immune effector function including also networking between normal epithelium and draining lymph nodes.
Physiological changes in the breast are primarily accompanied by activation of the unspecific, innate immune response, whereas the specific, adaptive immune response is activated during carcinogenesis and tumor progression. The content of immune cells increases progressively from normal breast tissue to premalignant lesions, as ductal carcinoma in situ (DCIS), and invasive carcinomas. The increase is primarily due to higher number of T-lymphocytes including cytotoxic (CD8+) cells activated by tumor antigens but also higher number of macrophages. Through acquisition of immune evasive mechanisms, the invasive cancer cells may during tumor progression escape the host immune surveillance, leading to a lower infiltration of immune cells in invasive carcinomas as compared to in situ lesions. The composition of the immune cells in premalignant and malignant lesions is shaped by both antigens but also environmental stimuli in the tumor (e.g., hypoxia), and may vary with aggressiveness of the lesion, tumor mutational burden and estrogen responsiveness of the tumor. The immune population in the tumor may not be observed in the circulation, and immunogenicity of the tumor can, therefore, not be captured by evaluation of the blood.
During the last decade, it has become increasingly clear that RT through liberation of neoantigens and damage-associated molecular patterns (DAMP) activates the STING pathway and induces a cytotoxic, tumor-specific T-cell response. The local immune response may drive a systemic response, which in mouse models have been associated with an abscopal effect and regression of non-irradiated tumor deposits. It is as such well-known that RT leads to attraction of immune cells to the tumor, but there is also accumulating evidence that the immune cells already present in the treatment-naive tumor influences the benefit from RT (and chemo-RT). In preclinical studies, activation of an RT-induced immune response have been shown to be elicited in highly immunogenic tumors only. This is consistent with findings that RT are better capable of re-activating a pre-existing T cell response, rather than initiating a new immune response. In clinical studies, the impact of immune cells present in the tumor-microenvironment in association with RT has primarily been described in the neoadjuvant setting with prognostic information found after preoperative chemo-RT in e.g., head-and neck cancer and rectal cancer. Recently, the level of tumor-infiltrating lymphocytes and subsets hereof has also been shown to hold predictive value in terms of benefit from post-operative RT in large cohorts of breast cancer patients. In preclinical studies, it is especially the presence of CD8+ T-lymphocytes but also antigen presenting cells (e.g., dendritic cells) that have been found to be important for mediation of the RT-induced immunogenic effect, and depletion of CD8+ cells have been found to abolish both tumor regression after RT and abscopal effects.
Radiosensitivity of immune cells vary between type and localization of the cells, and tissue-dependent immune cells are found to be more resistant than circulating cells. This contributes to a complex and delicate balance between the immunostimulating and -suppressive effects induced by RT. A balance, which is further affected by RT technology and -regime (dose, fractionation, field etc.). Manipulation of this balance is extensively studied in preclinical studies and through combination of RT and immunotherapy in several clinical studies.
In conclusion, growing evidence shows that the level and composition of the tumor immune response has important impact on mediation of an RT-induced immunogenic effect, and that tissue-based evaluation of tumour microenvironment may hold predictive value in terms of benefit from RT.