Mechanistic rationales for combining immunotherapy with radiotherapy

Abstract

Immunotherapy consisted mainly of immune checkpoint inhibitors (ICIs) has led to significantly improved antitumor response. However, such response has been observed only in tumors possessing an overall responsive tumor immune micro-environment (TIME), in which the presence of functional tumor-infiltrating lymphocytes (TILs) is critical. Various mechanisms of immune escape from immunosurveillance exist, leading to different TIME phenotypes in correlation with primary or acquired resistance to ICIs. Radiotherapy has been shown to induce antitumor immunity not only in the irradiated primary tumor, but also at unirradiated distant sites of metastases. Such antitumor immunity is mainly elicited by radiation’s stimulatory effects on antigenicity and adjuvanticity. Furthermore, it may be significantly augmented when irradiation is combined with immunotherapy, such as ICIs. Therefore, radiotherapy represents one potential therapeutic strategy to restore anti-tumor immunity in tumors presenting with an unresponsive TIME. In this review, the generation of anti-tumor immunity, its impairment, radiation’s immunogenic properties, and the antitumor effects of combining radiation with immunotherapy will be comprehensively discussed.

Biological effects of intraoperative radiation therapy: histopathological changes and immunomodulation in breast cancer patients

“…Radiotherapy is an efficient modulator of the immune response that may show antagonistic effects by facilitating or suppressing the anti-cancer immune response ( 13 , 14 ). These opposed effects in the TME seem to be influenced by the radiation modality, field, dose, and fractionation schedule, among other factors ( 15 , 16 ).…”

“…In addition to the outright lethal effects on cancer cells, radiotherapy can also modulate the TME by either stimulating or suppressing the antitumor immune response ( 13 , 14 ). The overall immunological impact of radiotherapy likely depends on many factors, including the tumor type and the modality and dose of radiotherapy ( 15 , 16 ).…”

Therapeutic In Situ Cancer Vaccine Using Pulsed Stereotactic Body Radiotherapy—A Translational Model

“…Hence, complementing the critical effect of SBRT cancer cell lysis and releasing collapsed lymphatic channels, along with drugs for lymphatic functional normalization, are crucial components of initiating the immunity cycle. The suboptimal activation of T cells through insufficient neoantigens leads to anergy due to coinhibitory signals [ 46 ], which significant neoantigen release through RT combination therapies can offset.…”

“…Activated T cells, as cytotoxic lymphocytes, have unique expressions of a set of homing chemokine receptors (e.g., CXC receptor 3 (CXCR3) and its ligands CXCL9, CXCL10, and CXCL11), complemented by related chemokines in the TME [ 46 ]. SBRT’s TME vascular, mechanical, immune-phenotypic, and metabolic effects will attract the CTLs trafficking to the tumor site, converting the immune “cold nodule” to a “hot nodule”.…”

“…At the tumor site, adhesion molecules, including selectin ligands, help bind to blood vessels and extravasate, resulting in TME infiltration. In the next step, cytotoxic CD8+ T cells recognize the target cancer cells through MHC-I molecules and induce T-cell-mediated cytotoxicity [ 46 ].…”