Immunobiology of cancer-associated fibroblasts in the context of radiotherapy

Hellevik, Turid; Berzaghi, Rodrigo; Lode, Kristin; Islam, Ashraful; Martínez-Zubiaurre, Iñigo

doi:10.1186/s12967-021-03112-w

Cited by 18 publications

(13 citation statements)

References 126 publications

(181 reference statements)

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“…Overall, our data implied that CAF-related DEGs might regulate radiotherapy response in prostate cancer through regulating ECM remodeling. Furthermore, CAFs are recognized contributors of tumor immune evasion [ 50 ]. CAFs can affect the anti-tumor immune response by influencing the recruitment of immune cells and driving an immunosuppressive function in immune cells [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

Zhang

Liu

2022

J Transl Med

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Background Cancer-associated fibroblasts (CAFs) play multiple roles in regulating tumor metastasis and treatment response. Current clinical indicators are insufficient to accurately assess disease risk and radiotherapy response, emphasizing the urgent need for additional molecular prognostic markers. Methods In order to investigate CAF-related genes associated with radiotherapy and construct prognostic CAF-related gene signatures for prostate cancer, we firstly established a radio-resistant prostate CAF cell subline (referred to as CAFR) from Mus-CAF (referred to as CAF) through fractionated irradiation using X-rays. Transcriptome sequencing for CAF and CAFR was conducted, and 2626 CAF-related differentially expressed genes (DEGs) associated with radiotherapy were identified. Human homologous genes of mouse CAF-related DEGs were then obtained. Results Functional enrichment analysis revealed that these CAF-related DEGs were significantly enriched ECM- and immune-related functions and pathways. Based on GSE116918 dataset, 186 CAF-related DEGs were correlated with biochemical recurrence-free survival (BCRFS) of prostate cancer patients, 16 of which were selected to construct a BCRFS-related CAF signature, such as ACPP, THBS2, and KCTD14; 142 CAF-related DEGs were correlated with metastasis-free survival (MFS), 16 of which were used to construct a MFS-related CAF signature, such as HOPX, TMEM132A, and ZNF467. Both Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets confirmed that the two CAF signatures accurately predicted BCRFS and MFS of prostate cancer patients. The risk scores were higher in patients with higher gleason grades and higher clinical T stages. Moreover, the BCRFS-related CAF signature was an independent prognostic factor and a nomogram consisting of BCRFS-related CAF signature and various clinical factors accurately predicted 2-, 3-, and 5-year survival time of prostate cancer patients. Furthermore, the risk score was positively correlated with multiple immune checkpoints. Conclusions Our established CAF signatures could accurately predict BCRFS and MFS in prostate cancer patients undergoing radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

Zhang

Liu

2022

J Transl Med

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“…These signals, in turn, lead to an increase in antigen presentation and therefore activation of the innate immune system, an increase of CD8+ cytotoxic T cell infiltration, and inhibition of immunosuppressive cells ( 13 ). Contrariwise, tipping the scale towards the immunosuppressive phenotype, the use of radiation results most of the time in the direct killing of T lymphocytes inside the radiation field, increments the myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) infiltration, and activates cancer-associated fibroblasts (CAFs) ( 14 ) through the TGF-β pathway, therefore, promoting tumor growth ( 15 – 17 ). Interestingly, RT has not only a modulating effect on the iTME but also systemically alters the immune profile of the patient.…”

Section: Introductionmentioning

confidence: 99%

The current understanding of the immune landscape relative to radiotherapy across tumor types

et al. 2023

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Radiotherapy is part of the standard of care treatment for a great majority of cancer patients. As a result of radiation, both tumor cells and the environment around them are affected directly by radiation, which mainly primes but also might limit the immune response. Multiple immune factors play a role in cancer progression and response to radiotherapy, including the immune tumor microenvironment and systemic immunity referred to as the immune landscape. A heterogeneous tumor microenvironment and the varying patient characteristics complicate the dynamic relationship between radiotherapy and this immune landscape. In this review, we will present the current overview of the immunological landscape in relation to radiotherapy in order to provide insight and encourage research to further improve cancer treatment. An investigation into the impact of radiation therapy on the immune landscape showed in several cancers a common pattern of immunological responses after radiation. Radiation leads to an upsurge in infiltrating T lymphocytes and the expression of programmed death ligand 1 (PD-L1) which can hint at a benefit for the patient when combined with immunotherapy. In spite of this, lymphopenia in the tumor microenvironment of ‘cold’ tumors or caused by radiation is considered to be an important obstacle to the patient’s survival. In several cancers, a rise in the immunosuppressive populations is seen after radiation, mainly pro-tumoral M2 macrophages and myeloid-derived suppressor cells (MDSCs). As a final point, we will highlight how the radiation parameters themselves can influence the immune system and, therefore, be exploited to the advantage of the patient.

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“…As one of the most abundant elements of the reactive stroma in solid tumors, cancer-associated fibroblasts (CAFs) [ 18 – 20 ] are exposed to the full prescribed radiation dose during the course of clinical radiotherapy [ 21 , 22 ]. However, the impact that radiation has on CAFs and the potential downstream effects of radiation-induced changes on therapy outcomes remain unsettled [ 11 , 23 – 25 ]. Studies investigating cytotoxic effects of ionizing radiation (IR) on stromal cells have revealed the intrinsic radio-resistant nature of fibroblasts [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated fibroblasts in radiotherapy: Bystanders or protagonists?

Martínez-Zubiaurre

Hellevik

2023

Cell Commun Signal

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Background The primary goal of radiotherapy (RT) is to induce cellular damage on malignant cells; however, it is becoming increasingly recognized the important role played by the tumor microenvironment (TME) in therapy outcomes. Therapeutic irradiation of tumor lesions provokes profound cellular and biological reconfigurations within the TME that ultimately may influence the fate of the therapy. Main content Cancer-associated fibroblasts (CAFs) are known to participate in all stages of cancer progression and are increasingly acknowledged to contribute to therapy resistance. Accumulated evidence suggests that, upon radiation, fibroblasts/CAFs avoid cell death but instead enter a permanent senescent state, which in turn may influence the behavior of tumor cells and other components of the TME. Despite the proposed participation of senescent fibroblasts on tumor radioprotection, it is still incompletely understood the impact that RT has on CAFs and the ultimate role that irradiated CAFs have on therapy outcomes. Some of the current controversies may emerge from generalizing observations obtained using normal fibroblasts and CAFs, which are different cell entities that may respond differently to radiation exposure. Conclusion In this review we present current knowledge on the field of CAFs role in radiotherapy; we discuss the potential tumorigenic functions of radiation-induced senescent fibroblasts and CAFs and we make an effort to integrate the knowledge emerging from preclinical experimentation with observations from the clinics.

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Immunobiology of cancer-associated fibroblasts in the context of radiotherapy

Cited by 18 publications

References 126 publications

Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

The current understanding of the immune landscape relative to radiotherapy across tumor types

Cancer-associated fibroblasts in radiotherapy: Bystanders or protagonists?

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