Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

Bule, Pedro; Aguiar, Sandra I.; Aires-da-Silva, Frederico; Dias, Joana

doi:10.3390/ijms22189804

Cited by 116 publications

(75 citation statements)

References 186 publications

(219 reference statements)

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“…Also, HHLA2 expression was found to be favorably associated to a number of chemokines, including CCL2, CCL20, and CXCL2. It was reported that such chemokines secreted by tumor cells and the microenvironment contribute to the recruitment of immunosuppressive cells into the tumor, such as MDSC, Treg, and TAM ( 38 – 40 ). Furthermore, these immunosuppressive cells can suppress CD8+ T-cell function, and interact with other immune regulatory cells which leads to exhaustion of cytotoxic T cells in tumor tissues ( 41 – 44 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Ding

Yang

et al. 2022

Front. Immunol.

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BackgroundInhibitory immune checkpoint proteins promote tumor immune escape and are associated with inferior patient outcome. However, the biological functions and regulatory roles of one of its members, HHLA2, in the tumor immune microenvironment have not been explored.MethodsRandomForest analyses (371 cases), qRT-PCR (15 cases), and immunohistochemical staining (189 cases) were used to validate the prognostic value of HHLA2 in hepatocellular carcinoma (HCC) patients. Bioinformatic analyses were further performed to explore the biological functions and potential signaling pathways affected by HHLA2. Moreover, ESTIMATE, single sample gene set enrichment analysis, CIBERSORT, TIMER, and other deconvolution methods were used to analyze the composition and infiltration level of immune cells. Multiplex immunofluorescence assays were employed to validate the fractions of suppressive immune cells, and HHLA2-related molecular alterations were investigated. Finally, the clinical response to chemotherapy and immune checkpoint blockade was predicted by TIDE, Submap, and several other in silico analyses.ResultsRandomForest analysis revealed that HHLA2 was the most important inhibitory immune checkpoint associated with HCC patient prognosis (relative importance = 1). Our HCC cohorts further revealed that high HHLA2 expression was an independent prognostic biomarker of shorter overall survival (P<0.01) and time to recurrence (P<0.001) for HCC patients. Bioinformatics experiments revealed that HHLA2 may accelerate the cell cycle of cancer cells. Additionally, we found that high expression of HHLA2 was associated with immune infiltrates, including some immunosuppressive cells, cytokines, chemokines, and corresponding receptors, resulting in an immunosuppressive environment. Notably, HHLA2 expression was positively correlated with the infiltration of exhausted CD8+ T cells, which was validated by immunofluorescence. Genomic alteration analyses revealed that promoter hypermethylation of HHLA2 may be associated with its low expression. More importantly, patients with high HHLA2 expression may be more sensitive to chemotherapy and have better responses to immunotherapy.ConclusionsHigh expression of HHLA2 is an independent prognostic biomarker for HCC patients. It can activate the cell cycle and foster an immunosuppressive tumor microenvironment by enriching exhausted CD8+ T cells. Promoter hypermethylation might lead to low expression of HHLA2 in HCC. Thus, targeting HHLA2 may be a practical therapeutic strategy for HCC patients in the future.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Ding

Yang

et al. 2022

Front. Immunol.

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“…Progression of HCC is not solely determined by biological features of cancer cells, such as their proliferation rate, but is also restricted and modulated by a TME composed of a network of immune and stroma cells. Of note, the chemokine CXCL10 has already been implicated in acute and chronic fibrosis as well as carcinogenesis [ 4 , 18 , 19 , 20 ]. Next, we set out to characterize the relevance of CXCL10 for the fibrotic non-tumorigenic microenvironment and the tumor stroma composition during hepatic carcinogenesis using HCC- bearing WT and Cxcl10 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma

Brandt

Baues

Wirtz

et al. 2022

IJMS

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Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10−/−) were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl4) to induce fibrosis-associated HCCs. Cxcl10 deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of Cxcl10 mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl4-treated Cxcl10−/− mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the Cxcl10−/− tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies.

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“…In recent years, chemokines have been used as important therapeutic targets for cancer. Mogamulizumab (an anti-CCR4 antibody) and Plerixafor/AMD3100 (a CXCR4 antagonist) have been approved for the treatment of hematologic malignancies and being in clinical trials ( Bule et al, 2021 ). In addition, Wsetermann et al used CCL19-conjugated DNA vaccine for tumor control and showed that the combination of the two significantly inhibited tumor growth and prolonged the antitumor effect of the vaccine ( Westermann et al, 2007 ).…”

Section: Chemokines In Clinical Research and Applicationsmentioning

confidence: 99%

Advances in Research on the Effects and Mechanisms of Chemokines and Their Receptors in Cancer

Chen

et al. 2022

Front. Pharmacol.

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Cancer is a common and intractable disease that seriously affects quality of life of patients and imposes heavy economic burden on families and the entire society. Current medications and intervention strategies for cancer have respective shortcomings. In recent years, it has been increasingly spotlighted that chemokines and their receptors play vital roles in the pathophysiology of cancer. Chemokines are a class of structurally similar short-chain secreted proteins that initiate intracellular signaling pathways through the activation of corresponding G protein-coupled receptors and participate in physiological and pathological processes such as cell migration and proliferation. Studies have shown that chemokines and their receptors have close relationships with cancer epigenetic regulation, growth, progression, invasion, metastasis, and angiogenesis. Chemokines and their receptors may also serve as potential targets for cancer treatment. We herein summarize recent research progresses on anti-tumor effects and mechanisms of chemokines and their receptors, suggesting avenues for future studies. Perspectives for upcoming explorations, such as development of multi-targeted chemokine-based anti-tumor drugs, are also discussed in the present review.

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Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

Cited by 116 publications

References 186 publications

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Comprehensive Analysis of HHLA2 as a Prognostic Biomarker and Its Association With Immune Infiltrates in Hepatocellular Carcinoma

Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma

Advances in Research on the Effects and Mechanisms of Chemokines and Their Receptors in Cancer

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