Challenges in the combination of radiotherapy and immunotherapy for breast cancer

Abstract

Introduction: Immunotherapy (IT) is showing promise in the treatment of breast cancer, but IT alone only benefits a minority of patients. Radiotherapy (RT) is usually included in the standard of care for breast cancer patients and is traditionally considered as a local form of treatment. The emerging knowledge of RT-induced systemic immune response, and the observation that the rare abscopal effect of RT on distant cancer metastases can be augmented by IT, have increased the enthusiasm for combinatorial immunoradiotherapy (IRT) for breast cancer patients. However, IRT largely follows the traditional sole RT and IT protocols and does not consider patient specificity, although patients' responses to treatment remain heterogeneous.

Areas covered: This review discusses the rationale of IRT for breast cancer, the current knowledge, challenges, and future directions.

Expert opinion: The synergy between RT and the immune system has been observed but not well understood at the basic level. The optimal dosages, timing, target, and impact of biomarkers are largely unknown. There is an urgent need to design efficacious pre-clinical and clinical trials to optimize IRT for cancer patients, maximize the synergy of radiation and immune response, and explore the abscopal effect in depth, taking into account patients' personal features.

Keywords: Immunotherapy; abscopal effect; breast cancer; immune response; precision medicine; radiotherapy.

Figure 1.. Effects of RT on the immune system.

RT causes immunogenic cell death releasing soluble mediators including cytokines, chemokines, tumor-associated antigens (TAAs), and damage-associated molecular patterns (DAMPs) inducing immunosuppressive and immunostimulatory effects and occasionally, abscopal effects. Immunosuppressive signaling molecules such as transforming growth factor β (TGFβ) are accompanied with recruitment of myeloid-derived suppressor cells (MDSCs), upregulation of programmed cell death-ligand 1 (PD-L1) on local tumor cells, and activation of regulatory T cells. Pro-inflammatory molecules namely DAMPs, and pro-inflammatory cytokines and chemokines are accompanied by enhanced expression of major histocompatibility complex I (MHC I), recruitment of antigen-presenting cells (APCs) like dendritic cells (DCs), and APC loading with antigens. Tumor antigen-loaded APCs increase T cell activation and proliferation and consequently, tumor cell recognition. Activated cytotoxic T cells travel in the circulatory system to distant sites of metastasis where, though rare, abscopal effects can occur.

Figure 2.. Synergistic effects of combined IRT.

RT is performed at the primary tumor site inducing a mixture of immunosuppressive and immunostimulatory effects. Abscopal effects are rare because, most of time, the induced concentration of T cells is not sufficient to overcome the immunosuppressive tumor microenvironment. ICB uses antibodies for targeting surface molecules PD-1 and CTLA-4 of regulatory and effector T cells and PD-L1 of cancer cells to block the immunosuppressive effects of checkpoint proteins, sustaining the activation and anti-tumor effector function of T cells. Separately, response rates to RT and IT are low in metastatic disease and durable, systemic responses are unlikely. When combined, immunomodulation and cross-priming of T cells is greatly enhanced leading to robust locoregional responses; systemic antitumor responses are also amplified, leading to greater possibility for abscopal effects at distant metastatic sites.

Figure 3.. Challenges for optimizing and personalizing IRT.

While protocols exist for IT and RT separately, impacts and effects of either treatment must be considered in congruence for future combination protocols. In RT, immunosuppressive and immunogenic effects must be balanced to promote greatest efficacy; RT dose, fractionation, and target volume must be adjusted to allow this balance in IRT. Likewise, IT dose must be evaluated to account for synergism of combined RT and IT protocols. Assessments of time windows for IRT are necessary and staged or simultaneous administrations may prove optimal based on tumor characteristics. Studies to determine biomarkers and genetic profiling for precision IRT are emerging, but multifactorial predictive indicators complicate the process. Individual traits such as host factors, tumor mutation burden, PD-L1 expression, tumor infiltrating lymphocyte, and radiation sensitivity all play a role in clinical treatment.