The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases

Korbecki, Jan; Bajdak-Rusinek, Karolina; Kupnicka, Patrycja; Kapczuk, Patrycja; Simińska, Donata; Chlubek, Dariusz; Baranowska-Bosiacka, Irena

doi:10.3390/ijms22073490

Cited by 68 publications

(58 citation statements)

References 188 publications

(234 reference statements)

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“… 33 CXCR6 is involved in STAT3, PI3K/AKT, ERK/MAPK pathway. 34 Meanwhile, PI3K/AKT pathway is also the downstream of JAK kinases. BAIAP3, a C2 domain-containing Munc13 protein, was also upregulated in CXCR6 + CD8 + T cells ( online supplemental figure S4F ).…”

Section: Discussionmentioning

confidence: 99%

CXCR6 is required for antitumor efficacy of intratumoral CD8⁺T cell

Wang

Sun

et al. 2021

J Immunother Cancer

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BackgroundIncreasing infiltration of CD8+ T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8+ T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases.MethodsCombination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6−/− mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6+CD8+ T cells. Transgenic Cxcr6−/− OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response.ResultsWe identified that CXCR6 was exclusively expressed on intratumoral CD8+ T cell. CXCR6+CD8+ T cells were more immunocompetent, and chimeras with specific deficiency on CD8+ T cells showed weaker antitumor activity. In addition, Cxcr6−/− mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6+CD8+ T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression.ConclusionsThis study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8+ T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

CXCR6 is required for antitumor efficacy of intratumoral CD8⁺T cell

Wang

Sun

et al. 2021

J Immunother Cancer

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“…Subsequently, these activated CXC chemokines will promote the progression and metastasis of cancer via numerous protumor properties. Seven CXC chemokines reported in this study, such as CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, and CXCL16, are all angiogenic [ 56 – 59 ]. High expression of these chemokines will cause neovascularization, thus promoting tumor invasion and metastasis [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer

Cao

et al. 2021

Journal of Oncology

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Despite dramatic responses to immune checkpoint inhibitors (ICIs) in patients with colon cancer (CC) harboring deficient mismatch repair (dMMR), more than half of these patients ultimately progress and experience primary or secondary drug resistance. There is no useful biomarker that is currently validated to accurately predict this resistance or stratify patients who may benefit from ICI-based immunotherapy. As hypoxic and acidic tumor microenvironment would greatly impair tumor-suppressing functions of tumor-infiltrating lymphocytes (TILs), we sought to explore distinct immunological phenotypes by analysis of the intratumoral hypoxia state using a well-established gene signature. Based on the Gene Expression Omnibus (GEO) (n = 88) and The Cancer Genome Atlas (TCGA) (n = 49) databases of patients with CC, we found that dMMR CC patients could be separated into normoxia subgroup (NS) and hypoxia subgroup (HS) with different levels of expression of hypoxia-related genes (lower in NS group and higher in HS group) using NMF package. Tumoral parenchyma in the HS group had a relatively lower level of immune cell infiltration, particularly CD8+ T cells and M1 macrophages than the NS group, and coincided with higher expression of immune checkpoint molecules and C-X-C motif chemokines, which might be associated with ICI resistance and prognosis. Furthermore, three genes, namely, MT1E, MT2A, and MAFF, were identified to be differentially expressed between NS and HS groups in both GEO and TCGA cohorts. Based on these genes, a prognostic model with stable and valuable predicting ability has been built for clinical application. In conclusion, the varying tumor-immune microenvironment (TIME) classified by hypoxia-related genes might be closely associated with different therapeutic responses of ICIs and prognosis of dMMR CC patients.

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“…For example, in liver cancer, sinusoidal endothelial cells were reported as primary producers of CXCL16 that recruited CXCR6 + anti-tumor NKT cells [98]. CXCL16 is also angiogenic, but its role in cancer remains controversial, as both pro-and anti-tumoral activities are reported [99].…”

Section: Cxcl13 and Cxcl16mentioning

confidence: 99%

The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer

Zutter

Damme

Struyf

2021

Cancers

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Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH2-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH2-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting.

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The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases

Cited by 68 publications

References 188 publications

CXCR6 is required for antitumor efficacy of intratumoral CD8⁺T cell

CXCR6 is required for antitumor efficacy of intratumoral CD8⁺T cell

Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer

The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer

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The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases

Cited by 68 publications

References 188 publications

CXCR6 is required for antitumor efficacy of intratumoral CD8+T cell

CXCR6 is required for antitumor efficacy of intratumoral CD8+T cell

Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer

The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer

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CXCR6 is required for antitumor efficacy of intratumoral CD8⁺T cell

CXCR6 is required for antitumor efficacy of intratumoral CD8⁺T cell