The intersection of radiotherapy and immunotherapy: Mechanisms and clinical implications

Abstract

By inducing DNA damage, radiotherapy both reduces tumor burden and enhances anti-tumor immunity. Here, we will review the mechanisms by which radiation induces anti-tumor immune responses that can be augmented using immunotherapies to facilitate tumor regression. Radiotherapy increases inflammation in tumors by activating the NF-κB and the Type I interferon response pathways to induce expression of pro-inflammatory cytokines. This inflammation coupled with antigen release from irradiated cells facilitates dendritic cell maturation and cross-presentation of tumor antigens to prime tumor-specific T cell responses. Radiation also sensitizes tumors to these T cell responses by enhancing T cell infiltration into tumors and the recognition of both malignant cancer cells and non-malignant stroma that present cognate antigen. Yet, these anti-tumor immune responses may be blunted by several mechanisms including regulatory T cells and checkpoint molecules that promote T cell tolerance and exhaustion. Consequently, the combination of immunotherapy using vaccines and/or checkpoint inhibitors with radiation is demonstrating early clinical potential. Overall, this review will provide a global view for how radiation and the immune system converge to target cancers and the early attempts to exploit this synergy in clinical practice.

Efficacy of combined radiotherapy and anti‐programmed death 1 therapy in acral and mucosal melanoma

“…RT‐induced DNA damage may generate neoantigens and augment the anti‐tumor immunity. Moreover, RT has the potential to increase the expression of cell surface receptors and tumor‐associated antigens . The combination of RT and ICI is based on the enhancing effect of RT on programmed death ligand 1 expression in the TME, which attenuates the sensitivity of anti‐tumor immune response .…”

“…Moreover, RT has the potential to increase the expression of cell surface receptors and tumor-associated antigens. 7,25,26 The combination of RT and ICI is based on the enhancing effect of RT on programmed death ligand 1 expression in the TME, which attenuates the sensitivity of anti-tumor immune response. 27 Moreover, Reits et al 28 reported that RT could upregulate the expression of major histocompatibility complex class I on the tumor cell surface to enhance presentation of tumor-specific peptides, increasing the effects of T cells.…”

Stereotactic ablative radiotherapy for hepatocellular carcinoma: History, current status, and opportunities

“…These effects may be especially relevant to high‐dose irradiation courses in comparison with more conventional courses and are the second major reason that SRS/SABR may be radiobiologically preferable to conventional treatments. A growing body of literature has also demonstrated that radiation can induce abscopal effects on distant, untreated sites of cancer and that this affect is associated with high‐dose irradiation and can be amplified by use of such therapies as immune checkpoint inhibitors and other immunomodulating drugs . This is an active area of clinical research as well …”

“…A growing body of literature has also demonstrated that radiation can induce abscopal effects on distant, untreated sites of cancer and that this affect is associated with high-dose irradiation and can be amplified by use of such therapies as immune checkpoint inhibitors and other immunomodulating drugs. (28,29) This is an active area of clinical research as well. (30)…”

Informatics for Cancer Immunotherapy

“…The understanding gained from studying the interaction of the immune system and cancer can be used to design interventions that improve the immune response to cancer. While conventional cancer therapies have immunological effects [301,302] , here, three approaches to cancer immunotherapy will be discussed: therapeutic vaccination, checkpoint modulation, and adoptive cell transfer (ACT).…”