The Role of CD97 in Regulating Adaptive T-Cell Responses

Spendlove, Ian; Sutavani, Ruhcha V.

doi:10.1007/978-1-4419-7913-1_12

Cited by 21 publications

(19 citation statements)

References 36 publications

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“…A second group of NP-binding membrane proteins we identified in our proteomic screen were adhesion molecules that stabilize the central signaling region of the IS [1], including the α L β 2 integrin (LFA-1) [41], adhesion molecule CD2 [42], and CD97, a receptor involved in both cell adhesion and signaling processes early after leukocyte activation [43]. Importantly, in none of 10 independent experiments were components of the T-cell receptor itself or its coreceptor CD8 identified as NP anchor proteins, which may in part explain the uncompromised antigen recognition capability of NP-decorated T cells.…”

Section: Resultsmentioning

confidence: 99%

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

et al. 2012

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Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.

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Section: Resultsmentioning

confidence: 99%

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

et al. 2012

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“…The majority of these proteins are classified as “orphan” receptors meaning the ligand(s) is unknown, and for most family members, precise biological functions remain mysterious. Despite our incomplete understanding of aGPCRs, they have been implicated in many crucial physiological processes, both during early development as well as in adult tissues, including but not limited to the role(s) of Celsr proteins [ 20 , 21 ] and Gpr125 [ 22 ] in gastrulation, Celsr1-3 in the migration of facial branchiomotor neurons during hindbrain development [ 50 ], Gpr126 in the development of the ear [ 19 ] and Schwann cells [ 18 , 51 - 53 ], Gpr124 in regulating CNS angiogenesis [ 54 ], CD97 in leukocyte trafficking and adaptive T-cells responses [ 55 ], EMR1 in the production of CD8+ cells [ 56 ], GPR64 in male infertility [ 57 ], and BAI1-3 in inhibiting angiogenesis in the brain [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish

et al. 2015

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BackgroundAdhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species.ResultsHere, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans; compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4. We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication. Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology.ConclusionsOur results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1296-8) contains supplementary material, which is available to authorized users.

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“…A study by Capasso et al showed that direct CD55 engagement with CD97 and co-stimulation with CD3 results in T-cell activation involving increased T-cell proliferation, IL-10, and GM-CSF production, and expression of activation markers CD69 and CD25 (77). Importantly, the naïve T cells that are stimulated in response to CD55 and CD97 binding are shown to produce cells that behave like Tregs, which would promote tumor progression if expressed in the TME (91).…”

Section: Cd55 and Cd97mentioning

confidence: 99%

The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy

2019

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It has long been understood that the control and surveillance of tumors within the body involves an intricate dance between the adaptive and innate immune systems. At the center of the interplay between the adaptive and innate immune response sits the complement system—an evolutionarily ancient response that aids in the destruction of microorganisms and damaged cells, including cancer cells. Membrane-bound complement regulatory proteins (mCRPs), such as CD46, CD55, and CD59, are expressed throughout the body in order to prevent over-activation of the complement system. These mCRPs act as a double-edged sword however, as they can also over-regulate the complement system to the extent that it is no longer effective at eliminating cancerous cells. Recent studies are now indicating that mCRPs may function as a biomarker of a malignant transformation in numerous cancer types, and further, are being shown to interfere with anti-tumor treatments. This highlights the critical roles that therapeutic blockade of mCRPs can play in cancer treatment. Furthermore, with the complement system having the ability to both directly and indirectly control adaptive T-cell responses, the use of a combinatorial approach of complement-related therapy along with other T-cell activating therapies becomes a logical approach to treatment. This review will highlight the biomarker-related role that mCRP expression may have in the classification of tumor phenotype and predicted response to different anti-cancer treatments in the context of an emerging understanding that complement activation within the Tumor Microenvironment (TME) is actually harmful for tumor control. We will discuss what is known about complement activation and mCRPs relating to cancer and immunotherapy, and will examine the potential for combinatorial approaches of anti-mCRP therapy with other anti-tumor therapies, especially checkpoint inhibitors such as anti PD-1 and PD-L1 monoclonal antibodies (mAbs). Overall, mCRPs play an essential role in the immune response to tumors, and understanding their role in the immune response, particularly in modulating currently used cancer therapeutics may lead to better clinical outcomes in patients with diverse cancer types.

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The Role of CD97 in Regulating Adaptive T-Cell Responses

Cited by 21 publications

References 36 publications

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles

Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish

The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy

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