Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Abstract

Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.

Radiation Therapy Modulates Tumor Physical Characteristics to Reduce Intratumoral Pressure and Enhance Intratumoral Drug Delivery and Retention

“…Low-dose XRT created an early window of low intratumoral pressure 1 to 3 days after XRT. A recent study showed that low-dose XRT modulates the tumor stroma and downregulates cancer-associated fibroblasts, 30 which causes the stroma to become more permeable and allows for effector immune cells (mainly natural killer and T cells) to infiltrate the TME. Once the natural killer and T cells infiltrate the stroma, immune-mediated killing begins.…”

A ‘Hybrid’ Radiotherapy Regimen Designed for Immunomodulation: Combining High-Dose Radiotherapy with Low-Dose Radiotherapy

“…HDRT negatively affects the tumor immune microenvironment by damaging the tumor vasculature [ 69 , 70 , 71 ] and reducing blood flow, which preclude immune cell infiltration and exacerbates the hypoxia-driven immunosuppressive environment [ 58 , 72 , 73 ]. In contrast, LDRT promotes immune effector cell infiltration, acting as a ‘TME modulator’ [ 18 ]. Dovedi et al demonstrated that low-dose fractionated radiotherapy (5*2 Gy) enhanced T-cell trafficking to irradiated tumor sites and augmented resident anticancer T-cell responses with the capacity to mediate the abscopal effect [ 74 ].…”

“…Interestingly, HDRT’s and LDRT’s effects on anti-tumor immunity seem to be complementary in many pathways. In contrast to HDRT, LDRT plays a critical role in modulating the tumor immune microenvironment via enhancing immune effector cell infiltration and attenuating the immune-suppressive effects of RT [ 18 ]. Thus, using a ‘hybrid’ RT regimen may be the way to optimally stimulate anti-tumor immunity.…”

Application of individualized multimodal radiotherapy combined with immunotherapy in metastatic tumors

“…Many studies have shown that low-dose radiotherapy (LDRT), i.e., lower than 2 Gy/fraction, can effectively reprogram the stroma from an immunosuppressive to immunostimulatory and synergize with immunotherapy ( 35 – 37 ). Interestingly, the mechanisms by which HDRT and LDRT regulate the antitumor immune system appear to be complementary ( 38 ). Therefore, the use of the multimodal radiotherapy regimen, such as HDRT and LDRT, can achieve optimal antitumor effects.…”