Application of individualized multimodal radiotherapy combined with immunotherapy in metastatic tumors

Abstract

Radiotherapy is one of the mainstays of cancer treatment. More than half of cancer patients receive radiation therapy. In addition to the well-known direct tumoricidal effect, radiotherapy has immunomodulatory properties. When combined with immunotherapy, radiotherapy, especially high-dose radiotherapy (HDRT), exert superior systemic effects on distal and unirradiated tumors, which is called abscopal effect. However, these effects are not always effective for cancer patients. Therefore, many studies have focused on exploring the optimized radiotherapy regimens to further enhance the antitumor immunity of HDRT and reduce its immunosuppressive effect. Several studies have shown that low-dose radiotherapy (LDRT) can effectively reprogram the tumor microenvironment, thereby potentially overcoming the immunosuppressive stroma induced by HDRT. However, bridging the gap between preclinical commitment and effective clinical delivery is challenging. In this review, we summarized the existing studies supporting the combined use of HDRT and LDRT to synergistically enhance antitumor immunity, and provided ideas for the individualized clinical application of multimodal radiotherapy (HDRT+LDRT) combined with immunotherapy.

Keywords: cancer; high-dose radiotherapy; immunotherapy; low-dose radiotherapy; metastatic tumor.

Figure 1

Antitumor immune enhancement of radiotherapy. Radiation therapy causes DNA DSBs in tumor cells and is sensed by the cGAS–STING pathway, resulting in the production of interferon I (IFN-I). In turn, IFN-I can stimulate dendritic cells (DCs) and T cell activation. Radiation therapy can induce immunogenic cell death. This releases danger-associated molecular patterns that promotes the activation and maturation of dendritic cells. DCs take up tumor-associated antigens (TAAs) from damaged tumor cells and travel to draining lymph nodes, and then present the TAAs on major histocompatibility complex class I (MHCI) to T cells through the T-cell receptor (TCR). Activated T cells move to the irradiated tumor and non-irradiated tumors through the blood circulation. Radiation can upregulate Fas and MHC-I molecules expression on tumors, and increase the release of cytokines and chemokines by tumor cells. This promotes the recruitment of activated T cells to kill tumor cells. In addition, radiation can upregulate the NK pathway to mediate tumor cells killing.

Figure 2

Immunosuppressive effects of radiotherapy. Radiation induces the recruitment of regulatory T cells (Tregs), myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Tregs produce transforming growth factor beta (TGFβ) and IL-10, which suppress effector-T-cell activation. MDSCs can suppress the activation of T-cell responses via secretion of arginase-1 (ARG1) and nitric oxide synthase 2 (NOS2). Radiation can promote the polarization of macrophages from an inflammatory M1 phenotype into a tumor-supporting M2 phenotype. These M2 macrophages secrete IL-10 and TGFβ and the enzyme arginase-1, which suppress T cell. TGFβ can suppress the effector functions of T-cells and natural killer (NK) cells, inhibiting DC maturation, and promoting M2 macrophage polarity. Radiation stimulates upregulation of immune checkpoint inhibitory molecules, such as programmed cell death ligand 1 (PD-L1) on tumor cells and PD-1 or CTLA-4 on cytotoxic T cells, which down regulate T cell activation. These effects suppress the antitumor immunity and promote tumor cell regrowth.

Figure 3

Immunomodulatory effects of LDRT in tumor microenvironment. LDRT modulates the tumor microenvironment by repolarizing macrophages to favor the M1 over the M2 phenotype, blocking regulatory T cells, and enhancing the infiltration of effector CD4 T cells and NK cells. Low-dose radiation can improve the efficacy of immune checkpoint inhibitors.

Figure 4

A personalized treatment regimen based on the patient’s performance status, clinical symptom, extent of tumor burden, and the immune type of the tumor microenvironment. (A) For a single tumor, HDRT can initiate T cell priming, followed by LDRT to modulate the tumor microenvironment. (B) For oligometastatic disease, HDRT can be delivered to all lesions. If it is infeasible and intolerable, it can be supplemented with LDRT. (C) For extensive metastatic disease, partial volume HDRT can be delivered to one or a few lesions, followed by LDRT to other lesions.