Lack of Functional Selectin Ligand Interactions Compromises Long Term Tumor Protection by CD8+ T Cells

Stark, Felicity C.; Gurnani, Komal; Sad, Subash; Krishnan, Lakshmi

doi:10.1371/journal.pone.0032211

Cited by 12 publications

(14 citation statements)

References 46 publications

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“…Functional selectin ligand deficiency results in elevated leukocyte levels in circulation, attributed in part to reduced neutrophil turnover . Consistent with our previous study, our data presented above show that enlarged splenic sizes in naive FtDKO mice is associated with increased cell numbers compared to their WT counterparts (Figure A and B) . A similar trend was observed between WT and FtDKO mice at day 3 postinfection with LM 10 4 CFUs i.v.…”

Section: Resultssupporting

confidence: 91%

“…Taken together, we show that innate immune responses sufficiently controlled bacterial numbers despite impaired lymphocyte homing in our acute infection model. However, it is important to note that adaptive immune responses mediated by lymphocytes are not dispensable during LM infection . We previously showed that sterilizing immunity to LM was mediated by antigen‐specific CD8 + T cells as well upon infection rechallenge .…”

Section: Discussionmentioning

confidence: 99%

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Lack of functional selectin-ligand interactions enhances innate immune resistance to systemic Listeria monocytogenes infection

Agbayani

Gurnani

Zafer

et al. 2017

Journal of Leukocyte Biology

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Selectin-ligand interactions are important for leukocyte homing and functionality. The roles of selectin-ligand interactions in modulating immunity to intracellular infections are not completely understood. Mice lacking the expression of fucosyltransferase-IV and -VII (Fucosyltransferase-IV and -VII double knockout, FtDKO) exhibit deficient functionality of selectin-ligand interactions. We addressed the kinetics of infection and immunity to Listeria monocytogenes (LM), an intracellular pathogen, in FtDKO mice. These mice exhibited enhanced ability to clear infection and increased survival to a lethal dose of LM infection relative to wild-type (WT) C57BL/6J controls. This was associated with increased levels of neutrophils, monocytes, and dendritic cells (DCs) in the blood and/or infected organs. Adoptive transfer of bone marrow (BM) cells from FtDKO mice to WT mice resulted in enhanced neutrophil numbers and improved clearance of LM bacteria in recipients. In vivo depletion of myeloid innate immune cells, particularly neutrophils, monocytes, macrophages, and DCs, using anti-Ly-6G (RB6-8C5) monoclonal antibody, reduced the ability of FtDKO mice to curtail LM infection. Nevertheless, depletion using anti-Ly-6G (1A8) known to exclusively deplete neutrophils did not abrogate increased resistance of FtDKO mice to LM infection, suggesting a role for other myeloid innate immune cells in this model. Examination of BM hematopoietic progenitors through flow cytometry and cell culture colony-forming unit assay showed increased frequencies of granulocyte-macrophage progenitors in FtDKO relative to WT mice, Overall, our results indicate that functional selectin ligand deficiency enhances innate immune-mediated resistance to systemic LM infection despite defective leukocyte migration and lymphocyte homing.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Lack of functional selectin-ligand interactions enhances innate immune resistance to systemic Listeria monocytogenes infection

Agbayani

Gurnani

Zafer

et al. 2017

Journal of Leukocyte Biology

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“…Higher vascular E-selectin expression among Merkel cell carcinomas in different patients was associated with larger numbers of CD8 T-cells, although it is unclear if the infiltrating T-cells were ESL + (Afanasiev et al, 2013). Fucosyltransferase IV and VII knockout CD8 T-cells cannot generate the carbohydrate structure to form functional ESL (Goelz et al, 1994, 1990; Knibbs et al, 1996; Maly et al, 1996) and their entry into SC B16-cOVA tumors is reduced compared to wild-type cells (Stark et al, 2012). However, whether wild-type CD8 T-cell entry was dependent on either ESL or PSL (which is also fucosyltransferase dependent) or both was not determined.…”

Section: Determinants Of Cd8 T-cell Representation In Tumors Andmentioning

confidence: 99%

Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment

Peske

Woods

Engelhard

2015

Advances in Cancer Research

131

111

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CD8 T-cells are a critical brake on the initial development of tumors. In established tumors, the presence of CD8 T-cells is correlated with a positive patient prognosis, although immunosuppressive mechanisms limit their effectiveness and they are rarely curative without manipulation. Cancer immunotherapies aim to shift the balance back to dominant anti-tumor immunity through antibody blockade of immunosuppressive signaling pathways, vaccination, and adoptive transfer of activated or engineered T-cells. These approaches have yielded striking responses in small subsets of patients with solid tumors, most notably those with melanoma. Importantly, the subset of patients who respond to vaccination or immunosuppression blockade therapies are those with CD8 T-cells present in the tumor prior to initiating therapy. While current adoptive cell therapy approaches can be dramatically effective, they require infusion of extremely large numbers of T-cells, but the number that actually infiltrate the tumor is very small. Thus, poor representation of CD8 T-cells in tumors is a fundamental hurdle to successful immunotherapy, over and above the well-established barrier of immunosuppression. In this review, we discuss the factors that determine whether immune cells are present in tumors, with a focus on the representation of cytotoxic CD8 T-cells. We emphasize the critically important role of tumor-associated vasculature as a gateway that enables the active infiltration of both effector and naïve CD8 T-cells that exert anti-tumor activity. We also discuss strategies to enhance the gateway function and extend the effectiveness of immunotherapies to a broader set of cancer patients.

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“…Previously, we have shown that when memory OVA-specific CD8 + T cell frequencies are similar and CD62L expression is low or their ligand is absent, long lasting tumor protection is impaired [26,35]. At late time points (>200 days) after a single dose of MS-OVA or LM-OVA, a low frequency of OVA-specific CD8 + T cells remain (~0.1%) and they are predominantly CD62L high .…”

Section: Discussionmentioning

confidence: 99%

Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

2016

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Homologous prime-boost vaccinations with live vectors typically fail to induce repeated strong CD8+ T cell responses due to the induction of anti-vector immunity, highlighting the need for alternative delivery vehicles. The unique ether lipids of archaea may be constituted into liposomes, archaeosomes, which do not induce anti-carrier responses, making them an ideal candidate for use in repeat vaccination systems. Herein, we evaluated in mice the maximum threshold of antigen-specific CD8+ T cell responses that may be induced by multiple homologous immunizations with ovalbumin (OVA) entrapped in archaeosomes derived from the ether glycerolipids of the archaeon Methanobrevibacter smithii (MS-OVA). Up to three immunizations with MS-OVA administered in optimized intervals (to allow for sufficient resting of the primed cells prior to boosting), induced a potent anti-OVA CD8+ T cell response of up to 45% of all circulating CD8+ T cells. Additional MS-OVA injections did not add any further benefit in increasing the memory of CD8+ T cell frequency. In contrast, OVA expressed by Listeria monocytogenes (LM-OVA), an intracellular bacterial vector failed to evoke a boosting effect after the second injection, resulting in significantly reduced antigen-specific CD8+ T cell frequencies. Furthermore, repeated vaccination with MS-OVA skewed the response increasingly towards an effector memory (CD62low) phenotype. Vaccinated animals were challenged with B16-OVA at late time points after vaccination (+7 months) and were afforded protection compared to control. Therefore, archaeosomes constituted a robust particulate delivery system to unravel the kinetics of CD8+ T cell response induction and memory maintenance and constitute an efficient vaccination regimen optimized for tumor protection.

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Lack of Functional Selectin Ligand Interactions Compromises Long Term Tumor Protection by CD8+ T Cells

Cited by 12 publications

References 46 publications

Lack of functional selectin-ligand interactions enhances innate immune resistance to systemic Listeria monocytogenes infection

Lack of functional selectin-ligand interactions enhances innate immune resistance to systemic Listeria monocytogenes infection

Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment

Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

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