Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions

Abstract

Since the approval of anti-CTLA4 therapy (ipilimumab) for late-stage melanoma in 2011, the development of anticancer immunotherapy agents has thrived. The success of many immune-checkpoint inhibitors has drastically changed the landscape of cancer treatment. For some types of cancer, monotherapy for targeting immune checkpoint pathways has proven more effective than traditional therapies, and combining immunotherapy with current treatment strategies may yield even better outcomes. Numerous preclinical studies have suggested that combining immunotherapy with radiotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. Radiation delivered to the tumor site affects both tumor cells and surrounding stromal cells. Radiation-induced cancer cell damage exposes tumor-specific antigens that make them visible to immune surveillance and promotes the priming and activation of cytotoxic T cells. Radiation-induced modulation of the tumor microenvironment may also facilitate the recruitment and infiltration of immune cells. This unique relationship is the rationale for combining radiation with immune checkpoint blockade. Enhanced tumor recognition and immune cell targeting with checkpoint blockade may unleash the immune system to eliminate the cancer cells. However, challenges remain to be addressed to maximize the efficacy of this promising combination. Here we summarize the mechanisms of radiation and immune system interaction, and we discuss current challenges in radiation and immune checkpoint blockade therapy and possible future approaches to boost this combination.

Surgical management of the neck in patients with metastatic melanoma in parotid lymph nodes

“…This is one of the principal reasons for its diminishing role in stage III disease, especially with increasing uptake of adjuvant immunotherapy, which has been shown to significantly reduce disease recurrence in stage IIIB and IIIC disease. Radiotherapy, however, still has a role in treating in‐transit metastatic disease, with a probable synergistic effect when administered concurrently with immunotherapy …”

“…Radiotherapy, however, still has a role in treating in-transit metastatic disease, with a probable synergistic effect when administered concurrently with immunotherapy. 26…”

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

“…It augments immunity by promoting the production of cytokines, including IFN‐β, IFN‐γ, and influencing DC activation, which stimulates cross‐priming of CD8 + T‐cells 118. Recently, excessive high‐dose radiation (20–30 Gy in 1 fraction) was demonstrated to disrupt tumor immunogenicity by prompting DNA exonuclease Trex1 to obstruct cGAS‐STING pathway induction 146. In autoimmunity of Aicardi‐Goutières syndrome, it has been exposed that RU.521 is dynamic and elective in cellular immune functionality of cGAS‐mediated immune signaling and decreases induction of IFN in macrophages in a mouse model.…”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…Cancer cells learn to evade the immune system by exploiting immune checkpoint pathways that prevent T lymphocytes from recognizing tumour‐specific antigens . There has been a recent change in clinical practice to incorporate immune checkpoint inhibitors into the management of a wide variety of advanced tumours, including melanoma, nonsmall cell lung cancer, lymphoma, head and neck tumours, gastrointestinal tumours, and genitourinary tumours . Their use can also be extended to soft tissue sarcoma and osteosarcoma .…”

“…124,125 There has been a recent change in clinical practice to incorporate immune checkpoint inhibitors into the management of a wide variety of advanced tumours, including melanoma, nonsmall cell lung cancer, lymphoma, head and neck tumours, gastrointestinal tumours, and genitourinary tumours. 60,126,127 Their use can also be extended to soft tissue sarcoma and osteosarcoma. 5,128 Since tumour infiltrating lymphocytes may represent a biomarker for the immune responsiveness of a tumour, there has been tremendous interest in further defining the role and potential of these pathway with an anti-PD-1 or PD-L1 antibody can restore multiple effector functions of antigen-specific T cells, overcoming immune escape mechanisms by cancer cells.…”