Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

Cuesta-Mateos, Carlos; Brown, Jennifer R.; Terrón, Fernando; Muñoz‐Calleja, Cecilia

doi:10.3389/fimmu.2021.662866

Cited by 14 publications

(15 citation statements)

References 230 publications

(453 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, pioneering pre-clinical studies using CCR7 function-blocking single-chain antibodies demonstrated that these pre-clinical biologicals blocked T-ALL cell transmigration across a human brain endothelial cell monolayer, and Ca 2+ mobilization in vitro [ 308 ]. More recently, an anti-CCR7 antibody was used to reduce CLL migration to the lymph nodes and the anticipated clinical trials will further examine the efficacy/safety of this anti-CCR7 therapy [ 309 ]. Moreover, systemic anti-CCR7 therapy might be warranted if the benefits outweigh the risks of compromising normal immune responses, which will depend on the length of therapy to some extent.…”

Section: Discussionmentioning

confidence: 99%

C-C Chemokine Receptor 7 in Cancer

Bill

Allen

Vines

2022

Cells

View full text Add to dashboard Cite

C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph nodes, questions immediately arose regarding the ability of CCR7 to direct migration of cancer cells to lymph nodes. The literature since 2000 was examined to determine to what extent the expression of CCR7 in malignant tumors promoted migration to the lymph nodes. The data indicated that in different cancers, CCR7 plays distinct roles in directing cells to lymph nodes, the skin or to the central nervous system. In certain tumors, it may even serve a protective role. Future studies should focus on defining mechanisms that differentially regulate the unfavorable or beneficial role that CCR7 plays in cancer pathophysiology, to be able to improve outcomes in patients who harbor CCR7-positive cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

C-C Chemokine Receptor 7 in Cancer

Bill

Allen

Vines

2022

Cells

View full text Add to dashboard Cite

show abstract

“…While CLL B-cells overexpress CCR7 [ 28 ], T-cells from treatment-naïve patients have comparable expression as healthy counterparts [ 29 , 30 , 31 ]. We and others have previously shown ibrutinib to cause a clear reduction of surface CCR7 levels in CLL B-cells that may eventually affect trafficking of malignant cells into the LN [ 22 , 32 , 33 ].…”

Section: Resultsmentioning

confidence: 99%

Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

Mateu‐Albero

Jiménez

Wissmann

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Bruton’s tyrosine kinase inhibitor ibrutinib has significantly changed treatment landscape in chronic lymphocytic leukemia (CLL). Growing evidence supports ibrutinib to work beyond the effect on tumor cells by means of, for example, restoring functionality of the T-cell compartment and increasing circulating T-cell numbers. Recent evidence suggests T-cell enhanced expansion, rather than increased egress from secondary lymphoid organs (SLO), as a root cause for ibrutinib-induced lymphocytosis. However, whether the latter physiological change is also a consequence of a forced retention in blood remains undisclosed. Since CCR7 is the main chemokine receptor taking over the homing of T-cells from peripheral compartments to lymph nodes and other SLO, we aimed to investigate the impact of ibrutinib on CCR7 functionality in T-cells. To this end, we documented receptor expression in T-cells from a large cohort of ibrutinib-treated CLL patients, and performed different in vivo and in vitro migration models. Overall, our data confirm that CCR7 expression or receptor-mediated migration in CLL T-cells is not affected by ibrutinib. Furthermore, it does not modulate CCR7-driven homing nor nodal interstitial migration. Together, our results support that ibrutinib-induced CLL T-cell accumulation in the blood stream is not derived from an impairment of CCR7-driven recirculation between the SLO and bloodstream, and therefore T-cell expansion is the most plausible cause.

show abstract

“…Whereas most blood circulating T cells express CCR7, peripheral DCs induce this chemokine receptor only upon encounter of danger signals ( 13 , 14 , 26 ). CCR7 induction has been shown to predominantly involve the transcription factors NF-κB and AP-1 ( 47 , 48 ). Interestingly, among all chemokine receptors, CCR7 possesses a unique signal sequence that facilitates its package into COPII vesicles for efficient ER to Golgi trafficking, and thus surface expression ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

CAL-1 as Cellular Model System to Study CCR7-Guided Human Dendritic Cell Migration

et al. 2021

View full text Add to dashboard Cite

Dendritic cells (DCs) are potent and versatile professional antigen-presenting cells and central for the induction of adaptive immunity. The ability to migrate and transport peripherally acquired antigens to draining lymph nodes for subsequent cognate T cell priming is a key feature of DCs. Consequently, DC-based immunotherapies are used to elicit tumor-antigen specific T cell responses in cancer patients. Understanding chemokine-guided DC migration is critical to explore DCs as cellular vaccines for immunotherapeutic approaches. Currently, research is hampered by the lack of appropriate human cellular model systems to effectively study spatio-temporal signaling and CCR7-driven migration of human DCs. Here, we report that the previously established human neoplastic cell line CAL-1 expresses the human DC surface antigens CD11c and HLA-DR together with co-stimulatory molecules. Importantly, if exposed for three days to GM-CSF, CAL-1 cells induce the endogenous expression of the chemokine receptor CCR7 upon encountering the clinically approved TLR7/8 agonist Resiquimod R848 and readily migrate along chemokine gradients. Further, we demonstrate that CAL-1 cells can be genetically modified to express fluorescent (GFP)-tagged reporter proteins to study and visualize signaling or can be gene-edited using CRISPR/Cas9. Hence, we herein present the human CAL-1 cell line as versatile and valuable cellular model system to effectively study human DC migration and signaling.

show abstract

Of Lymph Nodes and CLL Cells: Deciphering the Role of CCR7 in the Pathogenesis of CLL and Understanding Its Potential as Therapeutic Target

Cited by 14 publications

References 230 publications

C-C Chemokine Receptor 7 in Cancer

C-C Chemokine Receptor 7 in Cancer

Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

CAL-1 as Cellular Model System to Study CCR7-Guided Human Dendritic Cell Migration

Contact Info

Product

Resources

About