TLR activation and ionizing radiation induce strong immune responses against multiple tumor entities

Schölch, Sebastian; Rauber, Conrad; Weitz, Jürgen; Koch, Moritz; Huber, Peter E.

doi:10.1080/2162402x.2015.1042201

Cited by 25 publications

(18 citation statements)

References 10 publications

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“…Immuno-stimulatory responses are usually described as abscopal effects (from the Latin ab scopus, away from target), potentially impacting not only unexposed portions of the irradiated tumors but also metastatic lesions distant from the irradiation site. The mechanisms behind this phenomenon are still the subject of investigation (7,8,(30)(31)(32)(33)(34)(35)(36). An exciting recent study in patients showed that a combination of pembrolizumab with either partial or full irradiation resulted in a similar degree of tumor control (37,38), which the authors termed ADscopal (close to target) effect.…”

Section: Discussionmentioning

confidence: 99%

An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models

Markovsky

Budhu

Samstein

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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Purpose: To study tumor growth delay resulting from partial irradiation in preclinical mouse models. Methods and Materials: We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2×2 cm collimator on a micro-irradiator. Radiation response was modulated by treating with anti-CD8 and anti-ICAM antibodies. Similar experiments were performed using the less immunogenic Lewis Lung Carcinoma (LLC) mouse model. Tumor growth delay and gγH2AX phosphorylation were measured and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7 days post-radiotherapy (RT). Tumor expression of cellular adhesion molecules was also measured at different times post-RT. Results: Partial irradiation led to tumor responses similar to fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10Gy, infiltration of CD8 + T cells was observed, along with increased expression of ICAM. The response to 10Gy in hemi-*

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Section: Discussionmentioning

confidence: 99%

An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models

Markovsky

Budhu

Samstein

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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“…TLRs : TLRs (toll-like receptors) are both cytosolic and membranous molecules which recognize pathogens by their pathogen associated molecular patterns and danger signals released from damaged cells. Due to their unique capacity of regulating the immune cascade in pro-inflammatory response, their potential application in TIT has been suggested 174 as well as in combined therapy with RT 175, 176. Accumulating preclinical evidence showed that agonists of TLRs, especially TLR3, 4, 7/8 and 9 agonists, efficiently promote tumor-targeting immune responses initiated by anticancer immunotherapy.…”

Section: Radiation Induced Immune-targetable Elementsmentioning

confidence: 99%

Immune targets in the tumor microenvironment treated by radiotherapy

2019

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Radiotherapy (RT), the major anti-cancer modality for more than half of cancer patients after diagnosis, has the advantage of local tumor control with relatively less systematic side effects comparing to chemotherapy. However, the efficacy of RT is limited by acquired tumor resistance leading to the risks of relapse and metastasis. To further enhance the efficacy of RT, with the renaissances of targeted immunotherapy (TIT), increasing interests are raised on RT combined with TIT including cancer vaccines, T-cell therapy, and antibody-based immune checkpoint blockers (ICB) such as anti-CTLA-4 and anti-PD1/PD-L1. In achieving a significant synergy between RT and TIT, the dynamics of radiation-induced response in tumor cells and stromal cells, especially the cross-talk between tumor cells and immune cells in the irradiated tumor microenvironment (ITME) as highlighted in recent literature are to be elucidated. The abscopal effect refereeing the RT-induced priming function outside of ITME could be compromised by the immune-suppressive factors such as CD47 and PD-L1 on tumor cells and Treg induced or enhanced in the ITME. Cell surface receptors temporally or permanently induced and bioactive elements released from dead cells could serve antigenic source (radiation-associated antigenic proteins, RAAPs) to the host and have functions in immune regulation on the tumor. This review is attempted to summarize a cluster of factors that are inducible by radiation and targetable by antibodies, or have potential to be immune regulators to synergize tumor control with RT. Further characterization of immune regulators in ITME will deepen our understanding of the interplay among immune regulators in ITME and discover new effective targets for the combined modality with RT and TIT.

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“…55,56 We and others have demonstrated antitumour potential for TLR7 agonists in pre-clinical studies. [57][58][59] In a murine mesothelioma model, a combination of imiquimod (a TLR7 agonist) and anti-CD40 produced a systemic anti-tumour response in a CD8 T cell-dependent manner. 57,58 TLR7 also appears to have a dual role in lung cancer microenvironment.…”

Section: Other Non-specific Immunotherapymentioning

confidence: 99%

Immunotherapy for lung cancer

2016

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Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy.

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TLR activation and ionizing radiation induce strong immune responses against multiple tumor entities

Cited by 25 publications

References 10 publications

An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models

An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models

Immune targets in the tumor microenvironment treated by radiotherapy

Immunotherapy for lung cancer

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