Optimizing Radiation Therapy to Boost Systemic Immune Responses in Breast Cancer: A Critical Review for Breast Radiation Oncologists

Abstract

Immunotherapy using immune checkpoint blockade has revolutionized the treatment of many types of cancer. Radiation therapy (RT)-particularly when delivered at high doses using newer techniques-may be capable of generating systemic antitumor effects when combined with immunotherapy in breast cancer. These systemic effects might be due to the local immune-priming effects of RT resulting in the expansion and circulation of effector immune cells to distant sites. Although this concept merits further exploration, several challenges need to be overcome. One is an understanding of how the heterogeneity of breast cancers may relate to tumor immunogenicity. Another concerns the need to develop knowledge and expertise in delivery, sequencing, and timing of RT with immunotherapy. Clinical trials addressing these issues are under way. We here review and discuss the particular opportunities and issues regarding this topic, including the design of informative clinical and translational studies.

Fig. 1.

An example of an abscopal effect observed on PET/CT scanning in a patient with metastatic TNBC treated with pembrolizumab and hypofractionated RT (30 Gy/5 fractions) to a breast mass. The red circle denotes the RT field. At 19 weeks, regression of tumor in the mediastinal lymph nodes outside the RT portal is observed. Abbreviations: CT = computed tomography; PET = positron emission tomography; RT = radiation therapy; TNBC = triple negative breast cancer.

Fig. 2.

Model overview presenting the relationship between the primary tumor (T), antigen released (A), circulating lymphocytes (L), and the tumor cells in the positive node (N). Image created by Clemens Grassberger, PhD and Corey Speers, MD, PhD.

Fig. 3.

RT modulation of antitumor immune responses. RT exerts pleiotropic immunomodulatory effects on the tumor microenvironment. (1) RT-induced DNA damage in tumor cells stimulates innate immune signaling, in part through expression of type I interferon genes. (2) RT-induced chemokines promote infiltration of circulating lymphocytes and innate immune cells into the tumor microenvironment. (3) RT/IO can stimulate tumor cell phagocytosis by professional APCs, and (4) cross-presentation of tumor neoantigens in tumor-draining lymph nodes (TDLNs). (5) RT/IO can facilitate activation of primed tumor-reactive T cells to eradicate tumor cells at both the primary site and distant sites. Figure created with Biorender.com. Abbreviations: APC = antigen-presenting cells; RT = radiation therapy; RT/IO = radiation therapy/immunotherapy; TDLN = tumor-draining lymph nodes.

Fig. 4.

Trial schema for P-RAD, a randomized study of preoperative chemotherapy, pembrolizumab, and no-, low-, or high-dose radiation in node-positive, HER2− breast cancer. Abbreviations: AC = doxorubicin and cyclophosphamide; NAC = neoadjuvant chemotherapy; RT = radiation therapy.