Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy

Tilsed, Caitlin M.; Casey, Thomas H.; Jong, Emma de; Bosco, Anthony; Zemek, Rachael M.; Salmons, Joanne; Wan, Graeme; Millward, Michael; Nowak, Anna K.; Lake, Richard; Lesterhuis, W. Joost

doi:10.3389/fonc.2022.849793

Cited by 8 publications

(9 citation statements)

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“…Gene set enrichment analysis (GSEA) [ 38 ] was performed using curated gene sets. The first, ‘tretinoin induced’ gene set was created by selecting the DEG upregulated by tretinoin treatment using data generated in a previous study [ 12 ]. The second was obtained from Kang et al [ 39 ]; CD4 + T cells were cultured in the presence or absence of RA and genes upregulated in response to treatment collated into the ‘tretinoin treated CD4 + T cells Kang 2011’ gene set.…”

Section: Methodsmentioning

confidence: 99%

“…A potential avenue for increasing the effectiveness of chemotherapy would be to identify key drivers of this chemo-sensitive phenotype and therapeutically target them to upregulate expression and remodel the TME, using repurposed drugs. This approach was utilised in the context of ICT [ 11 , 12 ]. Network analysis of gene expression data from responding and non-responding mice identified tretinoin as a key promoter of an ICT sensitive tumor.…”

Section: Introductionmentioning

confidence: 99%

“…Network analysis of gene expression data from responding and non-responding mice identified tretinoin as a key promoter of an ICT sensitive tumor. In vivo validation in mesothelioma and sarcoma murine models showed a significant increase in anti-CTLA-4 efficacy when tretinoin was co-administered, demonstrating that this experimental strategy can identify drugs that can be repurposed for cancer treatment and synergise with existing therapies [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Tilsed,

Morales,

Zemek

et al. 2024

BMC Cancer

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Background Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy. Methods We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models. Results The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines. Conclusions Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Tilsed,

Morales,

Zemek

et al. 2024

BMC Cancer

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“…In the context of oncolytic NDV therapy innate immune sensing of viral RNA via RIG-I and activation of innate immune cells may enhance DC accumulation in tumors and make them more susceptible to ICI. A recent study reported that retinoic acid (the vitamin A derivative tretinoin) induces an IFN-I driven inflammatory TME, sensitizing it to ICI [ 88 ].…”

Section: Counteracting Immunosuppression Via Oncolytic Newcastle Dise...mentioning

confidence: 99%

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

Schirrmacher¹,

Gool²,

Stuecker³

2022

IJMS

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An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as “concomitant immunity” suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

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“…Recently, the combination of the HDACi belinostat with 13- cis -retinoic acid (isotretinoin, prodrug of ATRA) was well tolerated in patients with advanced solid tumors, including three with PDAC [ 165 ], which might prompt more studies to further assess its efficacy in PDAC. Moreover, retinoids enhanced the response to immune checkpoint inhibition, by inducing interferon mediated inflammation in TME, which was characterized by increased CD8+ T cell and decreased T-reg infiltration in cancer models [ 166 ]. On that basis, a phase I study is currently underway to test the efficacy of ATRA and nivolumab combination in patients with advanced or metastatic PDAC [ 167 ] ( Table 2 ).…”

Section: Epigenetic-based Therapeutic Approachesmentioning

confidence: 99%

Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment

Elrakaybi

Ruess

Lübbert

et al. 2022

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with high potential of metastases and therapeutic resistance. Although genetic mutations drive PDAC initiation, they alone do not explain its aggressive nature. Epigenetic mechanisms, including aberrant DNA methylation and histone modifications, significantly contribute to inter- and intratumoral heterogeneity, disease progression and metastasis. Thus, increased understanding of the epigenetic landscape in PDAC could offer new potential biomarkers and tailored therapeutic approaches. In this review, we shed light on the role of epigenetic modifications in PDAC biology and on the potential clinical applications of epigenetic biomarkers in liquid biopsy. In addition, we provide an overview of clinical trials assessing epigenetically targeted treatments alone or in combination with other anticancer therapies to improve outcomes of patients with PDAC.

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Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy

Cited by 8 publications

References 50 publications

Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

Epigenetics in Pancreatic Ductal Adenocarcinoma: Impact on Biology and Utilization in Diagnostics and Treatment

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