T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control

Steele, Maria M.; Jaiswal, Abhinav; Delclaux, Ines; Dryg, Ian D.; Murugan, Dhaarini; Femel, Julia; Son, Sunny; Bois, Haley du; Hill, Cameron; Leachman, Sancy A.; Chang, Young Hwan; Coussens, Lisa M.; Anandasabapathy, Niroshana; Lund, Amanda W.

doi:10.1038/s41590-023-01443-y

Cited by 55 publications

(48 citation statements)

References 68 publications

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“…It seemed that bexmarilimab increased immune cell abundance in tumors, which is contrary to published research describing impaired immune cell trafficking after Clever-1 blockade. While there is some selectivity in Clever-1 regulated trafficking 20 , a recent report by Steele and colleagues show that tumor lymphatics control the egress of T-cells after antigen exposure by ACKR3 upregulation, thus reducing CXCL12 sensitivity and promoting retention 21 . This might also be the case with Clever-1 targeting as we have previously shown that lymph node lymphatics in Clever-1 knock-out mice upregulate Ackr2 after OVA-CFA administration 22 .…”

Section: Discussionmentioning

confidence: 99%

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial

Rannikko

Verlingue

Miguel

et al. 2023

Preprint

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Clever-1 expression in macrophages contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial was designed to investigate the safety and tolerability of Clever-1 blockade in patients with treatment-refractory solid tumors and to assess preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab was well tolerated with no observed dose limiting toxicities in part I (n=30) and no additional safety signals in part II (n=108). Disease control (DC) rates of 25-40% were observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor positive breast, and biliary tract cancers, which associated with improved survival in a landmark analysis. High pre-treatment intra-tumoral Clever-1 staining and low circulating TNFα correlated with DC. Digital spatial profiling of DC and non-DC tumors with next generation sequencing showed bexmarilimab-induced macrophage activation and robust stimulation of IFNγ and T-cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well-tolerated and show that macrophage targeting can promote tumor control in late stage cancer.

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Section: Discussionmentioning

confidence: 99%

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial

Rannikko

Verlingue

Miguel

et al. 2023

Preprint

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“…Little is known about the fate or function of the cells that leave, although multiple studies have observed cells exiting sites of inflammation, ranging from CFA-induced injury to tumors to the gut at steady-state. [72][73][74][75][76] The requirements for these cells to exit are similarly poorly understood. While there are indications that S1P signaling is involved, it is unclear when S1P signaling is important, how S1P signaling cooperates or competes with other chemoattractants, how expression of S1P receptors is regulated in tissues, and how S1P gradients are regulated in tissues.…”

Section: S1p S I G Naling In E Xit From Non -Lymphoid Org Ans During ...mentioning

confidence: 99%

“…This has been particularly debated in the context of cancer. Would limiting T cell egress from a tumor induce exhaustion, or would it force productive interactions between T cells and tumor cells 74,76 ? It is similarly fascinating to consider how tissue exit affects the memory response.…”

Section: Regulation Of S1p Gradients In Non-lymphoid Tissuesmentioning

confidence: 99%

“…The cells that remain might fight infection, perpetuate inflammation, become exhausted, or differentiate into resident memory T cells. Little is known about the fate or function of the cells that leave, although multiple studies have observed cells exiting sites of inflammation, ranging from CFA‐induced injury to tumors to the gut at steady‐state 72–76 . The requirements for these cells to exit are similarly poorly understood.…”

Section: S1p Signaling In Exit From Non‐lymphoid Organs During An Imm...mentioning

confidence: 99%

“…In the Peyer's patches, CXCR4 was important to lead B cells to the vicinity of lymphatics, although S1P receptors were still required for crossing 68 . In a model of melanoma, Cxcl12 expression was upregulated by lymphatic endothelial cells in the tumor periphery, and lymphatic CXCL12 positioned CXCR4+ T cells close to exit sites and sequestered them away from the tumor core 74 . Whether CXCR4 can substitute for CCR7 or S1P receptors in crossing the lymphatic endothelium in non‐lymphoid tissues remains to be determined.…”

Section: S1p Signaling In Exit From Non‐lymphoid Organs During An Imm...mentioning

confidence: 99%

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Get me out of here: Sphingosine 1‐phosphate signaling and T cell exit from tissues during an immune response

Hallisey

Schwab

2023

Immunological Reviews

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SummaryDuring an immune response, the duration of T cell residence in lymphoid and non‐lymphoid tissues likely affects T cell activation, differentiation, and memory development. The factors that govern T cell transit through inflamed tissues remain incompletely understood, but one important determinant of T cell exit from tissues is sphingosine 1‐phosphate (S1P) signaling. In homeostasis, S1P levels are high in blood and lymph compared to lymphoid organs, and lymphocytes follow S1P gradients out of tissues into circulation using varying combinations of five G‐protein coupled S1P receptors. During an immune response, both the shape of S1P gradients and the expression of S1P receptors are dynamically regulated. Here we review what is known, and key questions that remain unanswered, about how S1P signaling is regulated in inflammation and in turn how S1P shapes immune responses.

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Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

Gong,

Jia,

Zhou

et al. 2023

Advanced NanoBiomed Research

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The therapeutic modes of cancers have been profoundly renovated by immunotherapies, which have shown extraordinary treating efficacy in certain tumor entities. However, the majority of cancer patients have not profited from it because of the negative effects of tumor microenvironment (TME) on human innate and/or adaptive immunity, including hypoxia, acidification, irregular vasculature, and a plethora of immunosuppressive cells and small molecules, which contribute to tumor progression, migration, resistance to drug, and so forth. Accordingly, it is feasible to enhance the efficacy of immunotherapies and increase the patients’ survival through the restructure of TME. Herein, the mechanisms and reverberations of aforementioned immunosuppressive elements are concentrated on, and latest therapeutic achievements and combined technologies that have been demonstrated effective in boosting immunotherapies by TME modulation are enumerated.

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T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control

Cited by 55 publications

References 68 publications

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: the phase I/II first-in-human MATINS trial

Get me out of here: Sphingosine 1‐phosphate signaling and T cell exit from tissues during an immune response

Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

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