Combining radiotherapy and immunotherapy: A revived partnership (original) (raw)

Radiation effects on antitumor immune responses: current perspectives and challenges

Therapeutic Advances in Medical Oncology, 2018

Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future...

Immunologically augmented cancer treatment using modern radiotherapy

Radiation oncology has recently seen tremendous technical advances, resulting in increasing cancer cures. However, malignant neoplasias are systemic diseases and may be lethal even with an excellent tumor local control. Immune therapy has grown to a mature approach in oncology, delivering results impossible only a few years ago. Treatment-limiting mechanisms such as the immune suppressive tumor microenvironment are now to a large extent deciphered, allowing for pharmacological intervention. Interestingly, radiation-based treatment effects have been shown to depend to a large degree on the immune system. Applying the recent advances in radiation therapy in conjunction with immune therapy can be a turning point towards the long-standing aim of curing cancer. Only a detailed understanding of the molecular mechanisms can guide the implementation of combined therapy modalities.

Immunomodulatory effects of radiation: what is next for cancer therapy?

Future Oncology, 2016

Despite its former reputation as being immunosuppressive, it has become evident that radiation therapy can enhance antitumor immune responses. This quality can be harnessed by utilizing radiation as an adjuvant to cancer immunotherapies. Most studies combine the standard radiation dose and regimens indicated for the given disease state, with novel cancer immunotherapies. It has become apparent that low-dose radiation, as well as doses within the hypofractionated range, can modulate tumor cells making them better targets for immune cell reactivity. Herein, we describe the range of phenotypic changes induced in tumor cells by radiation, and explore the diverse mechanisms of immunogenic modulation reported at these doses. We also review the impact of these doses on the immune cell function of cytotoxic cells in vivo and in vitro.

Immunobiology of Radiotherapy: New Paradigms

Radiation Research, 2014

It has been well demonstrated that irradiated dying cancer cells release tumor antigens. The extracellular antigens and dying tumor cells are engulfed by circulating bone marrowderived antigen-presenting cells (APCs). After antigen uptake, APCs migrate to lymph nodes, where they engage with helper T cells for post-stimulation and APC activation. Induction of Th1 response and the activation of APCs further stimulate the induction of tumor specific cytotoxic T lymphocytes (CTLs) that could potentially clear tumor cells both at primary and metastatic sites (Fig. 1). Radiation-induced immune modulation happens in two important phases. First, radiation induces damage-associated molecular pattern (DAMP) molecules. In this event, radiation normalizes tumor vasculature, modulates tumor cell phenotype and increases immune recognition of the tumor cell. Radiation treatment can cause: a. upregulation of chemokines and adhesion molecules, providing signals for T cells to be attracted to the tumor; and b. upregulation of MHC molecules and tumor-associated antigens, making it easier for endogenous or immunotherapy-induced T cells to recognize and kill tumor (immunogenic modulation). Second, amplification by abrogating immune checkpoint factors with simultaneous costimulation of effector factors can ultimately lead to the induction of multiple unique T-cell populations (antigen cascade) that can kill antigen disparate tumor cells at metastatic sites (systemic effect) (Fig. 2). Radiation-Induced Immunomodulation This issue highlights novel findings and concepts on the immunobiology of radiation therapy coupled with translational concepts. Wattenberg et al. (1) reported on several cases where radiation modulates tumor cells to undergo immunogenic cell death or immunogenic modulation and this immune response is directly proportional to radiation dose. Current clinical radiotherapy regimens involve both hypo-and hyperfractionated treatments. Therefore, it is important to understand how immune genes respond to survival adaptation of irradiated tumor cells (during multifractionation as well as after single high-dose fraction) to

Cancer immunotherapy: how low-level ionizing radiation can play a key role

Cancer immunology, immunotherapy : CII, 2017

The cancer immunoediting hypothesis assumes that the immune system guards the host against the incipient cancer, but also "edits" the immunogenicity of surviving neoplastic cells and supports remodeling of tumor microenvironment towards an immunosuppressive and pro-neoplastic state. Local irradiation of tumors during standard radiotherapy, by killing neoplastic cells and generating inflammation, stimulates anti-cancer immunity and/or partially reverses cancer-promoting immunosuppression. These effects are induced by moderate (0.1-2.0 Gy) or high (>2 Gy) doses of ionizing radiation which can also harm normal tissues, impede immune functions, and increase the risk of secondary neoplasms. In contrast, such complications do not occur with exposures to low doses (≤0.1 Gy for acute irradiation or ≤0.1 mGy/min dose rate for chronic exposures) of low-LET ionizing radiation. Furthermore, considerable evidence indicates that such low-level radiation (LLR) exposures retard the dev...

The Effects of Radiation on Cancer Immunology

Novel Approaches in Cancer Study, 2020

This event eventually stimulates the escape phase in which the cancer cells progress and undermine the effects of the immune system [5]. As a result of this tumor cell resistance technique, advancements in radiation therapy have become more extensively adapted to combat the further proliferation of cancer cells.

Harnessing the potential of radiation-induced immune modulation for cancer therapy

Cancer immunology research, 2013

The conventional use of radiotherapy is for local tumor control. Radiotherapy of the primary tumor can prevent the development of distant metastases, but this modality is generally not effective for treating preexisting systemic disease. However, radiation-induced tumor destruction may be considered a novel strategy for in situ cancer vaccination, in which tumor antigens released from dying tumor cells may be presented in an immunostimulatory context. Moreover, radiation has been demonstrated to induce immunogenic modulation in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Finally, radiotherapy typically has a favorable toxicity profile and is associated with the absence of systemic immunosuppression. Together, these properties suggest that radiotherapy may serve as an important component of combinatorial immunotherapies aimed at augmenting systemic antitumor immunity. Here, we provide an overview of the ra...

Radiotherapy supports tumor-specific immunity by acute inflammation

OncoImmunology, 2015

Zusammenfassung vorübergehende Entzündung auslöst, die die tumorspezifische Immunität unterstützt. Das Komplement System ist ein zentraler Bestandteil dieser Entzündungsreaktion. Eine Hemmung der Entzündungsreaktion mit Dexamethason, einem Kortikosteroid, welches im Zusammenhang mit Radiotherapie oft Patienten verabreicht wird, führte in einem präklinischen Modell zum Rückgang der therapeutischen Effizienz der Radiotherapie. Daraus schliessen wir, dass die durch Radiotherapie ausgelöste akute Entzündung wesentlich zur therapeutischen Effizienz beiträgt. Im zweiten Teil der Arbeit wird der Einfluss von Radiotherapie auf die Struktur und Funktion von Tumor-assoziierten Lymphgefässen untersucht. Wir stellten fest, dass die Struktur durch Radiotherapie nicht beeinflusst wurde, jedoch die Lymphdrainage verstärkt wurde.

Radiation, inflammation and the immune response in cancer

Mammalian Genome, 2018

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short-and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.