The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma

Lekan, Alexander A.; Weiner, Louis M.

doi:10.3390/cancers16030559

Cancers

2024

DOI: 10.3390/cancers16030559

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The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma

Alexander A. Lekan,

Louis M. Weiner

Abstract: Chemokines are small molecules that function as chemotactic factors which regulate the migration, infiltration, and accumulation of immune cells. Here, we comprehensively assess the structural and functional role of chemokines, examine the effects of chemokines that are present in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), specifically those produced by cancer cells and stromal components, and evaluate their impact on immune cell trafficking, both in promoting and suppressing ant… Show more

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2024

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Cited by 3 publications

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Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T‐cell therapy in solid tumors

Meng,

Hara,

Miura

et al. 2024

Cancer Science

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With recent advances in tumor immunotherapy, chimeric antigen receptor T (CAR‐T) cell therapy has achieved unprecedented success in several hematologic tumors, significantly improving patient prognosis. However, in solid tumors, the efficacy of CAR‐T cell therapy is limited because of high antigen uncertainty and the extremely restrictive tumor microenvironment (TME). This challenge has led to the exploration of new targets, among which fibroblast activation protein (FAP) has gained attention for its relatively stable and specific expression in the TME of various solid tumors, making it a potential new target for CAR‐T cell therapy. This study comprehensively analyzed the biological characteristics of FAP and discussed its potential application in CAR‐T cell therapy, including the theoretical basis, and preclinical and clinical research progress of targeting FAP with CAR‐T cell therapy for solid tumor treatment. The challenges and future optimization directions of this treatment strategy were also explored, providing new perspectives and strategies for CAR‐T cell therapy in solid tumors.

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Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T‐cell therapy in solid tumors

Meng,

Hara,

Miura

et al. 2024

Cancer Science

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The Y44 residue point mutation in CXCL14 reveals the significance of CXCL14 protein stability in anti-tumor activity

Kamal,

Ullah,

Kong

et al. 2024

Oncologie

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Objectives CXCL14, a member of the CXC chemokine family, plays a significant role in tumor development, progression, and metastasis, making it a potential target for cancer diagnosis and treatment. This study aims to investigate the impact of a point mutation in the (41VSRYR45) motif of CXCL14 on its anti-tumor activity. Methods Phylogenetic analysis, tertiary structure prediction, homology modeling, and cell culture experiments were employed to assess the effects of CXCL14 mutations on protein stability and anti-tumor activity. Phylogenetic analysis identified conserved regions critical for function, while computational tools predicted structural changes due to mutations. Homology modeling provided structural insights, and cell culture experiments involved transfecting HeLa cells with wild-type or mutant CXCL14 plasmids, assessing stability and anti-tumor effects. Additionally, in vivo, xenograft experiments using nude mice were conducted to evaluate the anti-tumor efficacy of CXCL14 variants. Results The conserved Y44 site within the (41VSRYR45) motif was identified as a key ubiquitination site. Mutations Y44V and Y44F enhanced CXCL14 stability, reducing HeLa cell proliferation and migration while increasing apoptosis. In vivo, tumor xenograft experiments confirmed the stronger inhibitory effect of these CXCL14 variants on tumor growth compared to the wild-type protein. Conclusion The Y44 site in CXCL14 is crucial for its stability and anti-tumor activity. Mutations Y44V and Y44F enhance CXCL14 stability and anti-tumor effects, suggesting that targeting this site could be a promising therapeutic strategy for cervical cancer.

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Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions

Argentiero,

Andriano,

Caradonna

et al. 2024

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.

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The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma

Cited by 3 publications

References 219 publications

Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T‐cell therapy in solid tumors

Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T‐cell therapy in solid tumors

The Y44 residue point mutation in CXCL14 reveals the significance of CXCL14 protein stability in anti-tumor activity

Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions

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