scholarly journals Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Luc Ollivier ◽  
Maureen Labbé ◽  
Delphine Fradin ◽  
Vincent Potiron ◽  
Stéphane Supiot

Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. In recent decades, the development of immunotherapies has resulted in great promise to cure metastatic disease. However, prostate cancer has failed to show any significant response, presumably due to its immunosuppressive microenvironment. There is therefore growing interest in combining immunotherapy with other therapies able to relieve the immunosuppressive microenvironment. Radiation therapy remains the mainstay treatment for prostate cancer patients, is known to exhibit immunomodulatory effects, depending on the dose, and is a potent inducer of immunogenic tumor cell death. Optimal doses of radiotherapy are thus expected to unleash the full potential of immunotherapy, improving primary target destruction with further hope of inducing immune-cell-mediated elimination of metastases at distance from the irradiated site. In this review, we summarize the current knowledge on both the tumor immune microenvironment in prostate cancer and the effects of radiotherapy on it, as well as on the use of immunotherapy. In addition, we discuss the utility to combine immunotherapy and radiotherapy to treat oligometastatic metastatic prostate cancer.

2021 ◽  
Author(s):  
Silke Lambing ◽  
Stefan Holdenrieder ◽  
Patrick Müller ◽  
Christian Hagen ◽  
Stephan Garbe ◽  
...  

The activation of the innate immune receptor RIG-I is a promising approach in immunooncology and currently under investigation in clinical trials. RIG-I agonists elicit a strong immune activation in both tumor and immune cells and induce both direct and indirect immune cell-mediated tumor cell death which involves tumor-specific cytotoxic T-cell response and type I interferon-driven innate cytotoxic immunity. Besides RIG-I, irradiation is known to induce cytotoxic DNA damage resulting in tumor debulking followed by the induction of tumor-specific immunity. To date, it is unclear whether the molecular antitumor effects of RIG-I and irradiation are additive or even synergize. Here, we investigated the combination of RIG-I activation with radiotherapy in melanoma. We found that low dose x-ray irradiation enhanced the extent and immunogenicity of RIG-I mediated tumor cell death in human and murine melanoma cell lines and in the murine B16 melanoma model in vivo. Pathway analysis of transcriptomic data revealed a central role for p53 downstream of the combined treatment, which was corroborated using p53-/- B16 cells. In vivo, the additional effect of irradiation on immune cell activation and inhibition of tumor growth was lost in mice carrying p53-knockout B16 tumors, while the response to RIG-I stimulation in those mice was maintained. Thus, our results identify p53 as pivotal for the synergy of RIG-I with irradiation, resulting in potent induction of immunogenic tumor cell death. Consequently, low dose radiotherapy holds great promise to further improve the efficacy or RIG-I ligands especially in patients with malignant melanoma or other tumors exhibiting a functional p53 pathway.


2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Austin W. T. Chiang ◽  
Hratch M. Baghdassarian ◽  
Benjamin P. Kellman ◽  
Bokan Bao ◽  
James T. Sorrentino ◽  
...  

AbstractCancer immunotherapy has revolutionized treatment and led to an unprecedented wave of immuno-oncology research during the past two decades. In 2018, two pioneer immunotherapy innovators, Tasuku Honjo and James P. Allison, were awarded the Nobel Prize for their landmark cancer immunotherapy work regarding “cancer therapy by inhibition of negative immune regulation” –CTLA4 and PD-1 immune checkpoints. However, the challenge in the coming decade is to develop cancer immunotherapies that can more consistently treat various patients and cancer types. Overcoming this challenge requires a systemic understanding of the underlying interactions between immune cells, tumor cells, and immunotherapeutics. The role of aberrant glycosylation in this process, and how it influences tumor immunity and immunotherapy is beginning to emerge. Herein, we review current knowledge of miRNA-mediated regulatory mechanisms of glycosylation machinery, and how these carbohydrate moieties impact immune cell and tumor cell interactions. We discuss these insights in the context of clinical findings and provide an outlook on modulating the regulation of glycosylation to offer new therapeutic opportunities. Finally, in the coming age of systems glycobiology, we highlight how emerging technologies in systems glycobiology are enabling deeper insights into cancer immuno-oncology, helping identify novel drug targets and key biomarkers of cancer, and facilitating the rational design of glyco-immunotherapies. These hold great promise clinically in the immuno-oncology field.


Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2965
Author(s):  
Cinzia Antognelli ◽  
Martina Mandarano ◽  
Enrico Prosperi ◽  
Angelo Sidoni ◽  
Vincenzo Nicola Talesa

Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.


2021 ◽  
Vol 22 (24) ◽  
pp. 13519
Author(s):  
Veronica Mollica ◽  
Andrea Marchetti ◽  
Matteo Rosellini ◽  
Giacomo Nuvola ◽  
Alessandro Rizzo ◽  
...  

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes’ alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation.


Author(s):  
Anh Phong Tran ◽  
M. Ali Al-Radhawi ◽  
Irina Kareva ◽  
Junjie Wu ◽  
David J. Waxman ◽  
...  

AbstractMetronomic chemotherapy can drastically enhance immunogenic tumor cell death. However, the responsible mechanisms are still incompletely understood. Here, we develop a mathematical model to elucidate the underlying complex interactions between tumor growth, immune system activation, and therapy-mediated immunogenic cell death. Our model is conceptually simple, yet it provides a surprisingly excellent fit to empirical data obtained from a GL261 mouse glioma model treated with cyclophosphamide on a metronomic schedule. The model includes terms representing immune recruitment as well as the emergence of drug resistance during prolonged metronomic treatments. Strikingly, a fixed set of parameters, not adjusted for individuals nor for drug schedule, excellently recapitulates experimental data across various drug regimens, including treatments administered at intervals ranging from 6 to 12 days. Additionally, the model predicts peak immune activation times, rediscovering experimental data that had not been used in parameter fitting or in model construction. The validated model was then used to make predictions about expected tumor-immune dynamics for novel drug administration schedules. Notably, the validated model suggests that immunostimulatory and immunosuppressive intermediates are responsible for the observed phenomena of resistance and immune cell recruitment, and thus for variation of responses with respect to different schedules of drug administration.


2006 ◽  
Vol 175 (4S) ◽  
pp. 208-208
Author(s):  
Brant A. Inman ◽  
Jeffrey M. Slezak ◽  
Eugene D. Kwon ◽  
Robert P. Myers ◽  
Bradley C. Leibovich ◽  
...  

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