Inflammatory microenvironment remodelling by tumour cells after radiotherapy

McLaughlin, Martin; Patin, Emmanuel C.; Pedersen, Malin; Wilkins, Anna; Dillon, Magnus T.; Melcher, Alan; Harrington, Kevin

doi:10.1038/s41568-020-0246-1

Cited by 512 publications

(433 citation statements)

References 166 publications

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“…Surveillance of ruptured radiation-induced micronuclei drives type-I IFN signalling in the tumour microenvironment 16 . This type-I IFN also drives immunosuppressive signalling, such as PD-L1 [20][21][22] and has been linked both to resistance to DNA-damaging agents clinically 42 and in ICI-radiotherapy combinations in mouse models 43 .…”

Section: Discussionmentioning

confidence: 99%

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4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

Melake

Smith

Mansfield

et al. 2020

Preprint

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Systemic relapse, after treatment of a localised primary tumour with neo-adjuvant radiotherapy and surgery, is the major cause of disease related mortality in patients with sarcoma. As with other cancers, many sarcoma patients derive no benefit from anti-PD-1 treatment. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates and control metastatic disease. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data to explore patient stratification for immunotherapy and therapeutic targets of relevance to sarcoma. We show a group of patients with immune-hot undifferentiated pleomorphic sarcoma as one of the highest-ranking candidates for emerging 4-1BB targeting agents. A binary hot/cold classification method indicates 4-1BB-high hot sarcomas share many characteristics with immunotherapy responsive cancers of other pathologies. Hot tumours in sarcoma are however substantially less prevalent. Patient stratification, of intense interest for immunotherapies, is therefore even more important in sarcoma.

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Section: Discussionmentioning

confidence: 99%

“…A substantial body of evidence supports the immunostimulatory properties of radiotherapy 16 . Given its established role in the management of patients with ESTS, the addition of radiotherapy to immunotherapy represents a promising and complementary combination.…”

Section: Introductionmentioning

confidence: 98%

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

Melake

Smith

Mansfield

et al. 2020

Preprint

Self Cite

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“…In our system, this anti-viral, pro-inflammatory state that is induced in fibroblasts by chemotherapy-treated cancer cells seems to promote the recovery of cancer cells after chemotherapy treatment. It was previously described that exposure of fibroblasts to high doses of chemotherapy could also drive an inflammatory microenvironment 28,45 . In contrast with these observations, in our system treatment of fibroblasts with the same chemotherapeutic doses that cancer cells were exposed to, did not drive the expression of ISGs in this cell type.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of stromal fibroblasts by chemotherapy-induced secretion of IFNβ1 drives re-growth of breast cancer cells after treatment

Maia

Koch

et al. 2020

Preprint

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Chemotherapy is still the standard of care for a large number of aggressive tumours including breast cancer. In breast cancer, chemotherapeutic regimens are administered in intervaled cycles of the maximum tolerated dose, allowing cancer cells to re-grow or adapt during the resting periods between cycles. However, how stromal fibroblasts impact the fate of cancer cells after chemotherapy treatment remains poorly understood. We show that cancer cells utilize paracrine signalling with stromal fibroblasts to drive their recovery after treatment withdrawal. Secretion of IFNβ1 by cancer cells after treatment with high doses of chemotherapy instigates the acquisition of an anti-viral state in stromal fibroblasts associated with the expression of several interferon stimulated genes (ISGs), including numerous pro-inflammatory cytokines. This crosstalk is an important driver of the expansion of breast cancer cells after chemotherapy and blocking of IFNβ1 in tumour cells abrogated their increased recovery potential. Analysis of human breast carcinomas supports the proposed role of IFNβ1 since its expression is inversely correlated with recurrence free survival (RFS). Moreover, expression of the interferon signature identified in stromal fibroblasts is equally associated with higher recurrence rates and a worse outcome in breast cancer patients. Our study unravels a novel paracrine communication between cancer cells and fibroblasts that ultimately results in the escape of malignant cells to treatment. Targeting of this axis could potentially improve the outcome of breast cancer patients to chemotherapy treatment.

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“…Irradiated tumor cells would also undergo immunogenic cell death with the release of tumor antigens and various danger-associated molecular patterns (DAMPs) molecules [ 87 , 88 ]. This immunogenic cell death will further increase the process of immune recognition by antigen presenting cells, as discussed above.…”

Section: Hot Tumor Induction By Radiation Therapymentioning

confidence: 99%

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

et al. 2020

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Cancer treatment has evolved tremendously in the last few decades. Immunotherapy has been considered to be the forth pillar in cancer treatment in addition to conventional surgery, radiotherapy, and chemotherapy. Though immunotherapy has resulted in impressive response, it is generally limited to a small subset of patients. Understanding the mechanisms of resistance toward cancer immunotherapy may shed new light to counter that resistance. In this review, we highlighted and summarized two major hurdles (recognition and attack) of cancer elimination by the immune system. The mechanisms of failure of some available immunotherapy strategies were also described. Moreover, the significance role of immune compartment for various established cancer treatments were also elucidated in this review. Then, the mechanisms of combinatorial treatment of various conventional cancer treatment with immunotherapy were discussed. Finally, a strategy to improve immune cancer killing by characterizing cancer immune landscape, then devising treatment based on that cancer immune landscape was put forward.

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Inflammatory microenvironment remodelling by tumour cells after radiotherapy

Cited by 512 publications

References 166 publications

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

Reprogramming of stromal fibroblasts by chemotherapy-induced secretion of IFNβ1 drives re-growth of breast cancer cells after treatment

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

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