Radiation effects on antitumor immune responses: current perspectives and challenges (original) (raw)
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Immune mechanisms mediating abscopal effects in radioimmunotherapy
Pharmacology & Therapeutics, 2018
Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens. Immunotherapies such as immunomodulatory monoclonal antibodies (anti-PD-1, anti-CTLA-4, anti-CD137, anti-OX40, anti-CD40, anti-TGFβ), TLR-agonists, and adoptive T-cell therapy have been synergistically combined with radiotherapy in mouse models. Importantly, radiation and immunotherapy combinations do not only act against the irradiated tumor but also against distant non-irradiated metastases (abscopal effects). A series of clinical trials are exploring the beneficial effects of radioimmunotherapy combinations. The concepts of crosspriming of tumor neoantigens and immunogenic cell death are key elements underlying this combination efficacy. Proinflamatory changes in the vasculature of the irradiated lesions and in the cellular composition of the leukocyte infiltrates in the tumor microenvironment contribute to raise or dampen cancer immunogenicity. It should be stressed that not all effects of radiotherapy favor antitumor immunity as there are counterbalancing mechanisms such as TGFβ, and VEGFs that inhibit the efficacy of the antitumor immune response, hence offering additional therapeutic targets to suppress. All in all, radiotherapy and immunotherapy are compatible and often synergistic approaches against cancer that jointly target irradiated and non-irradiated malignant lesions in the same patient.
Current Medicinal Chemistry
Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.
Radiation therapy and immunotherapy—a potential combination in cancer treatment
Current Oncology
BackgroundRadiation therapy (rt) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells.MethodsThe aim of the present work was to review current concepts of rt and immunotherapy synergism, the abscopal effect, and the molecular effects of rt in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response.ResultsUp-to-date literature concerning the mechanisms, interactions, and latest knowledge about rt and immunotherapy was reviewed and summarized, and is presented here.ConclusionsThe possibility of using hyperfractionated rt to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments.
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
Combining radiotherapy and immunotherapy: A revived partnership
International Journal of Radiation Oncology*Biology*Physics, 2005
Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radio-sensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This may have far reaching consequences on the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective anti-tumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from pre-clinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance anti-tumor effects. Conversely, RT could reveal a useful tool to combine with immunotherapy.
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.
Immunomodulatory effects of radiotherapy
2017
It is well known that radiotherapy, as mainly locoregional treatment, has systemic eff ects as well. The term abscopal eff ect (latin: ab – away from; scopus – target) has been used to describe the regression of distant tumor metastases after completion of primary tumor radiation therapy. It has been shown that radiotherapy can initiate systemic antitumor immunologic response which includes the activation of cytotoxic T-lymphocytes via numerous complex mechanisms. Latest fi ndings indicate that there is an extremely complex interaction between the eff ects of radiotherapy, the activation of diff erent signal pathways, tumor microenvironment and immunologic response. Depending on diff erent tumor and host immune system characteristics, radiation therapy may have either immunostimulatory or immunosuppressive eff ects. Several case reports and smaller studies have described tumor regression after concurrent application of immunotherapy and radiation therapy, mainly in metastatic melano...
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.
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...