Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer

Ware, Michael B.; El‐Rayes, Bassel F.; Lesinski, Gregory B.

doi:10.1136/jitc-2020-001100

Cited by 21 publications

(15 citation statements)

References 136 publications

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“…A variety of preclinical studies highlighting the influence of PDAC stromal components on T cell anti-tumour responses provided rationale for the development of clinical trials incorporating combined approaches to enhance T cell responses[ 80 ]. CXCL12 from cancer-associated fibroblasts synergizes with anti-PD-L1 blockade resulting in activation of T cells and tumour regression in mice[ 6 , 81 ].…”

Section: Discussionmentioning

confidence: 99%

T cells in pancreatic cancer stroma

Goulart¹,

Stasinos²,

Fincham³

et al. 2021

WJG

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Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a dismal 5-year survival rate. PDAC has a complex tumour microenvironment; characterised by a robust desmoplastic stroma, extensive infiltration of immunesuppressive cells such as immature myeloid cells, tumour-associated macrophages, neutrophils and regulatory T cells, and the presence of exhausted and senescent T cells. The cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance, disease progression and spread to distant organs. PDAC tumours, considered to be non-immunogenic or cold, express low mutation burden, low infiltration of CD8 + cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue, and often display an exhausted phenotype. Here, we review the role of T cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.

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Section: Discussionmentioning

confidence: 99%

T cells in pancreatic cancer stroma

Goulart¹,

Stasinos²,

Fincham³

et al. 2021

WJG

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“…With the rapid advancement in single-cell RNA sequencing, CAFs in solid human tumors are now classified into two subgroups, including myofibroblasts (myCAFs) and inflammatory fibroblasts (iCAFs) [ 13 ]. These two CAFs subtypes have been described in disparate locations relative to the cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression

Cao

Jiang

et al. 2021

Cancer Cell Int

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Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have witnessed significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage BLCA at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) is essential in impacting BLCA patients' prognosis and responsiveness to ICB therapy. CXCL12 is a stromal secreted factor that was essentially involved in regulating the TME among cancers. In this article, we thoroughly investigated the TME regulating roles of CXCL12 in BLCA and revealed its critical involvement in the development of BLCA, which was closely correlated with inflammatory fibroblasts (iCAFs). Methods We examined the gene expression profiles in the TCGA and GEO database to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of BLCA. The receiver operating characteristic curve was used to explore the accuracy of CXCL12 along with multiple iCAFs-associated genes in the diagnosis of BLCA. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. The "maftool" R package analyzed the oncogenic mutations in BLCA patients. Bioinformatics analysis results were further validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors. Results This manuscript revealed a significantly reduced expression of CXCL12 in BLCA compared with normal tissue. The expressions of various marker genes for iCAFs were also reduced considerably in BLCA tissues, highlighting the reduction of iCAFs in the pathogenesis of BLCA. Further studies revealed that CXCL12 and iCAFs were associated with pathological features, TME remodeling and aging in BLCA patients. The iCAFs signature further confirmed the intricate immunomodulatory roles of iCAFs in BLCA. Gene mutation analysis revealed the essential relationship between iCAFs and the mutation frequency of oncogenic genes, including TP53 and FGFR3. Meantimes, iCAFs levels also significantly affected BLCA patients' mutations in the TP53 and RTK-RAS pathways. Finally, our results confirmed the significant exclusion of CD8 + T cells by iCAFs, which further influenced the immunotherapy responsiveness in BLCA patients. Conclusions This article highlighted the impact of CXCL12 on the pathogenesis and progression of BLCA. The reduced expression levels of iCAFs markers, including CXCL12, were highly accurate in the diagnosis of BLCA, suggesting the reduction of iCAFs accompanied bladder carcinogenesis. However, both CXCL12 and iCAFs significantly impacted the prognosis and immunotherapy responsiveness for BLCA patients by remodeling the TME. Our results critically suggested the dual roles of iCAFs in the carcinogenesis and progression of BLCA. Further exploration of iCAFs might unravel potential diagnostic biomarkers and therapeutic targets for BLCA.

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“…Redesigning the tumor-cellular composition and reversing the immunosuppressive cell niche phenotype are two further ways to enhance the chimeric antigen receptor -T cell treatment efficiency [72]. To do this, designed chimeric antigen receptor -T cells to release cytokines or other soluble chemicals that promote paracrine or endocrine TME modification [73].…”

Section: Promoting Endogenous Immuno Responses By Restructuring Tmesmentioning

confidence: 99%

Therapeutic Applications of Engineered Chimeric Antigen Receptors-T cell for Cancer Therapy

Hussain¹

2021

Preprint

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Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.

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Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer

Cited by 21 publications

References 136 publications

T cells in pancreatic cancer stroma

T cells in pancreatic cancer stroma

Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression

Therapeutic Applications of Engineered Chimeric Antigen Receptors-T cell for Cancer Therapy

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