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Immunophenotyping of whole blood of the prostate adenocarcinoma patients treated with IMRT (a) and SABR (b). Whole blood was collected before the start of the treatment and after the last radiation fraction. Expression values were interpolated for IMRT patients for radiation dose of 36.25 Gy for better comparison with SABR-related values. The counts of B cells, T cells, neutrophils, natural killer (NK) cells, monocytes, and myeloid-derived suppressor cells (MDSCs) per ml of peripheral blood are displayed as well as the percentages of HLA-DR-expressing monocytes (Mo) and programmed death 1 receptor-expressingT helper cells (TH.PD1). Hash indicates comparisons showing at least a large effect size (|rW| ≥ 0.5)
Source publication
Background
In this exploratory study, the impact of local irradiation on systemic changes in stress and immune parameters was investigated in eight patients treated with intensity-modulated radiation therapy (IMRT) or stereotactic ablative body radiotherapy (SABR) for prostate adenocarcinoma to gain deeper insights into how radiotherapy (RT) modula...
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Citations
... This observation is contrary to previous observations in whole-body irradiated mice, where an increased ratio of LPCs to PCs was proposed as a radiation biomarker that generally indicates a pro-inflammatory response and phospholipase A activity [84]. Furthermore, the analysis of patients irradiated due to prostate cancer revealed that changes in the LPC/PC ratio depend on the irradiation scheme and dose: the LPC/PC ratio increased after conventional intensity-modulated RT and decreased after hypofractionated accelerated RT [85]. It is also important to note that serum concentrations of LPCs that increased in the initial phase of response to RT were elevated in the later post-RT samples (late RT effects or the healing stage) [67], which resembled the pattern of inflammation more closely. ...
Response to radiotherapy (RT) includes tissue toxicity, which may involve inflammatory reactions. We aimed to compare changes in metabolic patterns induced at the systemic level by radiation and inflammation itself. Patients treated with RT due to head and neck cancer and patients with inflammation-related diseases located in the corresponding anatomical regions were selected. PubMed and Web of Science databases were searched from 1 January 2000 to 10 August 2023. Twenty-five relevant studies where serum/plasma metabolic profiles were analyzed using different metabolomics approaches were identified. The studies showed different metabolic patterns of acute and chronic inflammatory diseases, yet changes in metabolites linked to the urea cycle and metabolism of arginine and proline were common features of both conditions. Although the reviewed reports showed only a few specific metabolites common for early RT response and inflammatory diseases, partly due to differences in metabolomics approaches, several common metabolic pathways linked to metabolites affected by radiation and inflammation were revealed. They included pathways involved in energy metabolism (e.g., metabolism of ketone bodies, mitochondrial electron transport chain, Warburg effect, citric acid cycle, urea cycle) and metabolism of certain amino acids (Arg, Pro, Gly, Ser, Met, Ala, Glu) and lipids (glycerolipids, branched-chain fatty acids). However, metabolites common for RT and inflammation-related diseases could show opposite patterns of changes. This could be exemplified by the lysophosphatidylcholine to phosphatidylcholine ratio (LPC/PC) that increased during chronic inflammation and decreased during the early phase of response to RT. One should be aware of dynamic metabolic changes during different phases of response to radiation, which involve increased levels of LPC in later phases. Hence, metabolomics studies that would address molecular features of both types of biological responses using comparable analytical and clinical approaches are needed to unravel the complexities of these phenomena, ultimately contributing to a deeper understanding of their impact on biological systems.
... Intensity-modulated radiation therapy enables the accurate delivery of the radiation dose to tumors while exerting an indirect effect. The immune cells in the TME are activated by intensity-modulated radiation therapy, altering the growth of tumor cells [93]. However, whether the correlation between immunity and tumors is affected by radiation fraction is yet to be elucidated. ...
Neoadjuvant chemoradiotherapy (nCRT) is recommended for the treatment of locally advanced rectal cancer. Even though the combination of nCRT and immune checkpoint inhibitors (ICIs) has received much attention, the specific combination modes and dose fractions in radiotherapy (RT) are still indistinct. This review focuses on the immunological mechanism involved in nCRT, the clinical efficacy, the immunological effect of different combined strategies, concurrent or sequential nCRT plus ICIs, long-course RT and short-course RT. This review discusses the impact of nCRT on tumor immunity and summarizes the availability of different dose fractions in RT and distinct combined strategies, aiming at providing clues for optimal neoadjuvant therapy options that maximize efficacy and minimize side effects.
... This mechanism was assumed to be present in a subset of renal cell carcinomas, where it was shown that a radical nephrectomy might improve survival [7]. Therefore, we reasoned that this mechanism might also apply to prostate cancer, as research showed a systemic modulation of the immune system after local radiotherapy [8]. ...
Purpose
To describe a local radio-oncological treatment for patients with prostate cancer that metastasized to either the lymph nodes or distant regions.
Methods and materials
We included 133 patients with prostate cancer that displayed either distant metastases (DM) or lymph node metastases alone (NM) and were treated between 2004 and 2019. All patients underwent computed tomography and a bone scan or 18F- or prostate-specific membrane antigen-targeted positron emission tomography. Patients received local external beam radiation therapy to the prostate to achieve local control (60–81.4 Gy to the prostate, and 45–50.4 Gy to pelvic lymph nodes), with either the 3D conformal (4-field box) or volumetric modulated arc therapy technique. A urologist prescribed additional therapy.
Results
We included 51 patients with DM and 82 patients with NM. The mean follow-up was 42 months for all patients. The groups were similar in T stage, initial prostate-specific antigen, histology, androgen deprivation therapy, age, treatment techniques, and prescribed doses, but different in lymph node inclusion and follow-up times. In the NM and DM groups, the 5‑year biochemical recurrence-free rates were 52% and 24%, respectively (p < 0.0001); the 5‑year disease-specific survival rates were 92% and 61%, respectively (p = 0.001); and the 5‑year OS rates were 77% and 48%, respectively (p = 0.01). The groups had similar acute and late gastrointestinal and genitourinary side effects, except that late genitourinary side effects occurred significantly more frequently in the NM group (p = 0.01).
Conclusions
DM was associated with significantly worse outcomes than NM. The long-term survival of patients with metastatic prostate cancer was low.
... Ho et al. [7] have stated that BC is the most prevalent malignant tumor among women, and its incidence, which has been increasing in recent years, accounts for 14% of all malignant tumors in the female body. According to pertinent literature, the BC incidence among Asian women increased by approximately 1.7% per year from 2006 and 2015, so it is urgent to provide effective treatment for BC patients [8]. ...
Objective:
To investigate the effect of stereotactic radiotherapy (SBRT) combined with thermoplastic fixation on set-up error in breast cancer (BC) patients undergoing radiotherapy.
Methods:
Ninety BC patients undergoing radiotherapy who were treated in our hospital (May 2019-May 2020) were selected as the research objects and equally divided into the experimental group and control group according to the order of hospitalization, with 45 patients in each group. The control group received conventional radiotherapy combined with breast bracket, and the experimental group received SBRT combined with thermoplastic fixation. The incidences of adverse reactions, 1-year survival rates, and set-up errors were compared between the two groups.
Results:
Compared with the control group, the experimental group had much lower total incidence of adverse reactions and remarkably higher 1-year survival rate. The translational errors (X direction, Y direction, and Z direction), translational errors after rotation (X direction, Y direction, and Z direction), and rotation errors (X direction, Y direction, and Z direction) in the experimental group were obviously lower compared with those in the control group.
Conclusion:
Implementing SBRT combined with thermoplastic fixation in BC patients undergoing radiotherapy can effectively improve set-up efficiency and treatment accuracy and reduce set-up errors. Compared with the breast bracket, the combination of SBRT and thermoplastic fixation has higher application value, and further studies are conducive to providing patients with a better solution plan.
... In preclinical studies, hypo-fractionated RT of 8 Gy ×3 was more effective to induce abscopal effects compared to a single fractionation of 20 Gy when it is combined with ICIs [56,57], but 8 Gy ×3 is also less immunogenic as 8 Gy ×2 when being combined with an autologous tumor cell-ased vaccine [58]. It has already also clinically been proven that locally delivered RT induces systemic modulation of the immune system in tumor patients, but different RT approaches appear to specifically affect distinct immune components [59]. ...
Purpose of Review
This review focuses on the opposing effects on the immune system of radiotherapy (RT) and the consequences for combined cancer treatment strategies of RT with immunotherapies, including hyperthermia (HT). How RT and HT might affect cancer stem cell populations is also briefly outlined in this context.
Recent Findings
RT is one of the crucial standard cancer therapies. Most patients with solid tumors receive RT for curative and palliative purposes in the course of their disease. RT achieves a local tumor control by inducing DNA damage which can lead to tumor cell death. In recent years, it has become evident that RT does not only have local effects, but also systemic effects which involves induction of anti-tumor immunity and possible alteration of the immunosuppressive properties of the tumor microenvironment. Though, often RT alone is not able to induce potent anti-tumor immune responses since the effects of RT on the immune system can be both immunostimulatory and immunosuppressive.
Summary
RT with additional therapies such as HT and immune checkpoint inhibitors (ICI) are promising approaches to induce anti-tumor immunity effectively. HT is not only a potent sensitizer for RT, but it might also improve the efficacy of RT and certain chemotherapeutic agents (CT) by additionally sensitizing resistant cancer stem cells (CSCs).
Graphical abstract
... RT can influence the immune status of patients. Several papers investigated the influence of RT on the intratumoral immune response in various tumor types and how RT-induced changes to local immune parameters impact tumor behavior and long-term response to therapy [14,15]. On the other hand, local RT can modulate systemic immune responses as well [16,17]. ...
... The majority of patients (76%) had grade 2 cumulative late GU side effects, and just one patient had more severe late GU symptoms. According to the pre-treatment IPSS scores 14% (3/21) of the patients had mild (score 1-7), 43% (9/21) had moderate (score [8][9][10][11][12][13][14][15][16][17][18][19] and 43% (9/21) had severe (score 20-35) urination symptoms. In contrast, the GI side effects were milder; 71% of patients had no GI side effects, 24% of them had grade 1 and 5% of patients had symptoms of grade 2 severity. ...
Background:
The development of cancer and anti-tumor therapies can lead to systemic immune alterations but little is known about how long immune dysfunction persists in cancer survivors.
Methods:
We followed changes in the cellular immune parameters of prostate cancer patients with good prognostic criteria treated with low dose rate brachytherapy before and up to 3 years after the initiation of therapy.
Results:
Patients before therapy had a reduced CD4+ T cell pool and increased regulatory T cell fraction and these alterations persisted or got amplified during the 36-month follow-up. A significant decrease in the total NK cell number and a redistribution of the circulating NK cells in favor of a less functional anergic subpopulation was seen in patients before therapy but tumor regression led to the regeneration of the NK cell pool and functional integrity. The fraction of lymphoid DCs was increased in patients both before therapy and throughout the whole follow-up. Increased PDGF-AA, BB, CCL5 and CXCL5 levels were measured in patients before treatment but protein levels rapidly normalized.
Conclusions:
while NK cell dysfunction recovered, long-term, residual alterations persisted in the adaptive and partly in the innate immune system.
... Nevertheless, precise monitoring of the temperature in the tumor during the treatment will not only improve the efficacy of the local treatment, but also gives a chance to predict the changes in immune phenotype of the cancer cells. Besides monitoring of local immune alterations inside and around the treated tumor, systemic effects should be complementarily considered in the future to increase knowledge about immune modulations induced by RT alone and in combination with HT and ICIs [70,71]. ...
Simple Summary
Hyperthermia (HT) is a cancer treatment which locally heats the tumor to supraphysiological temperature, and it is an effective sensitizer for radiotherapy (RT) and chemotherapy. HT is further capable of modulating the immune system. Thus, a better understanding of its effect on the immune phenotype of tumor cells, and particularly when combined with RT, would help to optimize combined anti-cancer treatments. Since in clinics, no standards about the sequence of RT and HT exist, we analyzed whether this differently affects the cell death and immunological phenotype of human breast cancer cells. We revealed that the sequence of HT and RT does not strongly matter from the immunological point of view, however, when HT is combined with RT, it changes the immunophenotype of breast cancer cells and also upregulates immune suppressive immune checkpoint molecules. Thus, the additional application of immune checkpoint inhibitors with RT and HT should be beneficial in clinics.
Abstract
Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39–44 °C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and particularly, how the sequence of HT and RT changes the immune phenotype of breast cancer cells. Therefore, human MDA-MB-231 and MCF-7 breast cancer cells were treated with HT of different temperatures (39, 41 and 44 °C), alone and in combination with RT (2 × 5 Gy) in different sequences, with either RT or HT first, followed by the other. Tumor cell death forms and the expression of immune checkpoint molecules (ICMs) were analyzed by multicolor flow cytometry. Human monocyte-derived dendritic cells (moDCs) were differentiated and co-cultured with the treated cancer cells. In both cell lines, RT was the main stressor for cell death induction, with apoptosis being the prominent cell death form in MCF-7 cells and both apoptosis and necrosis in MDA-MB-231 cells. Here, the sequence of the combined treatments, either RT or HT, did not have a significant impact on the final outcome. The expression of all of the three examined immune suppressive ICMs, namely PD-L1, PD-L2 and HVEM, was significantly increased on MCF-7 cells 120 h after the treatment of RT with HT of any temperature. Of special interest for MDA-MB-231 cells is that only combinations of RT with HT of both 41 and 44 °C induced a significantly increased expression of PD-L2 at all examined time points (24, 48, 72, and 120 h). Generally, high dynamics of ICM expression can be observed after combined RT and HT treatments. There was no significant difference between the different sequences of treatments (either HT + RT or RT + HT) in case of the upregulation of ICMs. Furthermore, the co-culture of moDCs with tumor cells of any treatment had no impact on the expression of activation markers. We conclude that the sequence of HT and RT does not strongly affect the immune phenotype of breast cancer cells. However, when HT is combined with RT, it results in an increased expression of distinct immune suppressive ICMs that should be considered by including immune checkpoint inhibitors in multimodal tumor treatments with RT and HT. Further, combined RT and HT affects the immune system in the effector phase rather than in the priming phase.
... 23 The reason is probably the more ambivalent nature of RT in terms of modulation of the immune system. Independent of that, systemic alterations in immune and stress parameters are more and more observed after local application of RT. 24 Next to the aforementioned stimulatory effects on the TME, also immunosuppressive effects of RT are known. Apoptosis is a physiological form of cell death important for tissue homeostasis during growth and development and in contrast to necrosis, the cellular membrane stays intact. ...
Radiotherapy (RT) is still one of the standard cancer therapies with up to two third of all cancer patients with solid tumors being irradiated in the course of their disease. The aim of using ionizing radiation in fractionated treatment schedules was always to achieve local tumor control by inducing DNA damage which can be repaired by surrounding normal tissue but leads to cell death in tumor cells. Meanwhile, it is known that RT also has immunological effects reshaping the tumor microenvironment. Nevertheless, RT alone often fails to elicit potent antitumor immune responses as these effects can be immunostimulatory as well as immunosuppressive. Here, we discuss how immunotherapies can be exploited in combined therapies to boost RT-induced antitumor immune responses or to counteract preexisting and RT-mediated immunosuppression to improve local and systemic tumor control. Furthermore, we highlight some parameters of radioimmunotherapies (RITs) which are under investigation for potential optimizations and how RIT approaches are tested in first phases II and III trials. Finally, we discuss how RT might affect normal and cancer stem cells. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Although radiotherapy primarily locally targets tumors to kill tumor cells, research of the last decade has proven that ionizing radiation can provoke tumor-specific immune responses by induction of immunogenic cancer cell death and it reshapes the immunological tumor microenvironment including cells with stem-cell like properties. These effects and knowledge about related mechanisms can be exploited to improve the therapeutic efficacy of immune therapies such as vaccines and immune checkpoint inhibitors in multimodal therapy settings including classical tumor therapies and are discussed in this work.
... Furthermore, radiotherapy also upregulated MHC class I on cancer cells, leading to the recognition of TAAs by cytotoxic T cells, enabling them to raise an antitumour response. Thus, prostate radiotherapy could potentially initiate a systemic, or 'abscopal' immune response, resulting in antitumorigenic responses in distant metastases [135]. According to Reits et al., the effect of γ-irradiation on MHC class I molecules could explain immune-mediated abscopal effects [136,137]. ...
Prostate cancer is among the most frequent cancers in men worldwide. Despite the fact that multiple therapeutic alternatives are available for its treatment, it is often discovered in an advanced stage as a metastatic disease. Prostate cancer screening is based on physical examination of prostate size and prostate-specific antigen (PSA) level in the blood as well as biopsy in suspect cases. However, these markers often fail to correctly identify the presence of cancer, or their positivity might lead to overdiagnosis and consequent overtreatment of an otherwise silent non-progressing disease. Moreover, these markers have very limited if any predictive value regarding therapy response or individual risk for therapy-related toxicities. Therefore, novel, optimally liquid biopsy-based (blood-derived) markers or marker panels are needed, which have better prognostic and predictive value than the ones currently used in the everyday routine. In this review the role of circulating tumour cells, extracellular vesicles and their microRNA content, as well as cellular and soluble immunological and inflammation- related blood markers for prostate cancer diagnosis, prognosis and prediction of therapy response is discussed. A special emphasis is placed on markers predicting response to radiotherapy and radiotherapy-related late side effects.
... While patients in the present series were largely treated before the current era of checkpoint inhibitors, advances in immunotherapies are an important consideration for future studies on oligometastatic head and neck cancer. As synergistic effects for the combination of radiotherapy and checkpoint inhibitor treatment have been described [20][21][22], the synthesis of local treatment and systemic immunotherapy could be especially beneficial in the oligometastatic setting. Ongoing trails like IMPORTANCE (NCT03386357) and CheckRad-CD8 (NCT03426657) are already investigating optimal combination strategies of radiotherapy and checkpoint inhibitor treatment and results are eagerly awaited. ...
Background
There is a large lack of evidence for optimal treatment in oligometastatic head and neck cancer and it is especially unclear which patients benefit from radical local treatment of all tumour sites.
Methods
40 patients with newly diagnosed oligometastatic head and neck cancer received radical local treatment of all tumour sites from 14.02.2008 to 24.08.2018. Primary endpoint was overall survival. Time to occurrence of new distant metastases and local control were evaluated as secondary endpoints as well as prognostic factors in univariate und multivariate Cox’s regression analysis. To investigate the impact of total tumour volume on survival, all tumour sites were segmented on baseline imaging.
Results
Radical local treatment included radiotherapy in 90% of patients, surgery in 25% and radiofrequency ablation in 3%. Median overall survival from first diagnosis of oligometastatic disease was 23.0 months, 2-year survival was 48%, 3-year survival was 37%, 4-year survival was 24% and 5-year survival was 16%. Median time to occurrence of new distant metastases was 11.6 months with freedom from new metastases showing a tail pattern after 3 years of follow-up (22% at 3, 4- and 5-years post-treatment). In multivariate analysis, better ECOG status, absence of bone and brain metastases and lower total tumour volume were significantly associated with improved survival, whereas the number of metastases and involved organ sites was not.
Conclusions
Radical local treatment in oligometastatic head and neck cancer shows promising outcomes and needs to be further pursued. Patients with good performance status, absence of brain and bone metastases and low total tumour volume were identified as optimal candidates for radical local treatment in oligometastatic head and neck cancer and should be considered for selection in future prospective trials.
