Firefighters for the Wrong Type of Inflammation in Tumors

Melero, Ignacio; Teijeira, Álvaro; Aranda, Fernando; Berraondo, Pedro

doi:10.1158/2159-8290.cd-21-1004

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…The clinical significance of this may extend to cytotoxic T-cell function within the TME, which is critical for ICI efficacy. Prior studies have shown that cytokines such as IL-1β, TNFα, and IL-6/IL-6R promote inflammation that is damaging to cytotoxic T lymphocyte immunity ( 91 – 94 ). In our study, these cytokines were notably up-regulated by treatment with ICI alone, in contrast to treatment with EC5026 alone or in combination with ICI.…”

Section: Discussionmentioning

confidence: 99%

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Kelly,

Wang,

Rothenberger

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Cancer therapy, including immunotherapy, is inherently limited by chronic inflammation-induced tumorigenesis and toxicity within the tumor microenvironment. Thus, stimulating the resolution of inflammation may enhance immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the resolution of cancer-associated inflammation. Here, we demonstrate that systemic treatment with ICI induces sEH expression in multiple murine cancer models. Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH inhibition, both alone and in combination, significantly enhance anti-tumor activity of ICI in these models. Notably, pharmacological abrogation of the sEH pathway alone or in combination with ICI counter-regulates an ICI-induced pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous EpFA levels through dietary supplementation or sEH inhibition may represent a unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Kelly,

Wang,

Rothenberger

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…olid tumors can be understood as abnormal organs with a microenvironment populated by transformed cancer cells and normal immune and stromal cells [1]. Understanding how the composition of this complex microenvironment relates to tumor status or progression is the key to personalized anticancer therapies [2]. This requires answering questions such as: which cell phenotypes populate the tumor or the stromal compartment?…”

Section: Introductionmentioning

confidence: 99%

Synplex: In Silico Modeling of the Tumor Microenvironment From Multiplex Images

Jiménez-Sánchez

Ariz

Andrea

et al. 2023

IEEE Trans. Med. Imaging

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Multiplex immunofluorescence is a novel, high-content imaging technique that allows simultaneous in situ labeling of multiple tissue antigens. This technique is of growing relevance in the study of the tumor microenvironment, and the discovery of biomarkers of disease progression or response to immune-based therapies. Given the number of markers and the potential complexity of the spatial interactions involved, the analysis of these images requires the use of machine learning tools that rely for their training on the availability of large image datasets, extremely laborious to annotate. We present Synplex, a computer simulator of multiplexed immunofluorescence images from user-defined parameters: i. cell phenotypes, defined by the level of expression of markers and morphological parameters; ii. cellular neighborhoods based on the spatial association of cell phenotypes; and iii. interactions between cellular neighborhoods. We validate Synplex by generating synthetic tissues that accurately simulate real cancer cohorts with underlying differences in the composition of their tumor microenvironment and show proof-of-principle examples of how Synplex could be used for data augmentation when training machine learning models, and for the in silico selection of clinically relevant biomarkers. Synplex is publicly available at https://github.com/djimenezsanchez/Synplex.

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“…Interestingly, the ongoing CANOPY-A and CANOPY-N (159,161) are evaluating canakinumab in the adjuvant and neoadjuvant settings in surgically amenable cases, respectively. Reasons for failure may indicate that more than one redundant pro-inflammatory mechanism may be at play in latestage cancer and combined inhibition may be (162).…”

Section: Il-1 and Il-1mentioning

confidence: 99%

Towards inmunotherapeutic exploitation strategies of rotumor and antitumor cytokines

Olivera

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In cancer pathogenesis, soluble mediators are responsible for a type of inflammation that favors the progression of tumors. The mechanisms chiefly involve changes in the cellular composition of the tumor tissue stroma and in the functional modulation of myeloid and lymphoid leukocytes. Active immunosuppression, pro-angiogenesis, changes in leukocyte traffic, extracellular-matrix remodeling and alterations in tumorantigen presentation are the main mechanisms linked to the inflammation that fosters tumor growth and metastasis. Soluble inflammatory mediators and their receptors are amenable to various types of inhibitors that can be combined with other immunotherapy approaches. The main pro-inflammatory targets which can be interfered with at present and which are under preclinical and clinical development are IL-1, IL-6, the CXCR1/2 chemokine axis, TNF, VEGF, LIF, CCL2, IL-35 and prostaglandins (PGs). In many instances, the corresponding neutralizing agents are already clinically available and can be repurposed as a result of their use in other areas of medicine such as autoimmune diseases and chronic inflammatory conditions.

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Firefighters for the Wrong Type of Inflammation in Tumors

Cited by 4 publications

References 21 publications

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase

Synplex: In Silico Modeling of the Tumor Microenvironment From Multiplex Images

Towards inmunotherapeutic exploitation strategies of rotumor and antitumor cytokines

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