Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response

Davra, Viralkumar; Kimani, Stanley; Calianese, David; Birge, Raymond B.

doi:10.3390/cancers8120107

Cited by 61 publications

(56 citation statements)

References 105 publications

(110 reference statements)

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“…In some cases, MACS sorted splenic M-or G-MDSCs from B6 mice were added to the MLRs to determine their suppression of 2C T cell proliferation. ***P ≤ .001 approach actively tested in cancer therapies, 40 directly activating the kinase domain of MerTK is currently a concept that awaits the development of target-specific small molecule activators of this domain. Representative histograms were gated on 2C CD8 + T cells.…”

Section: Reciprocally We Tested Whether Graft Protection By Donor Ecmentioning

confidence: 99%

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Zhang

DeBerge

Wang

et al. 2019

American Journal of Transplantation

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Recipient infusion of donor apoptotic cells is an emerging strategy for inducing robust transplantation tolerance. Daily clearance of billions of self-apoptotic cells relies on homeostatic engagement of phagocytic receptors, in particular, receptors of the tyrosine kinase family TAM (Tyro3, Axl, and MerTK), to maintain self-tolerance. However, an outstanding question is if allogeneic apoptotic cells trigger the same receptor system for inducing allogeneic tolerance. Here, we employed allogeneic apoptotic splenocytes and discovered that the efferocytic receptor MerTK on recipient phagocytes is a critical mediator for transplantation tolerance induced by this strategy. Our findings indicate that the tolerogenic properties of allogeneic apoptotic splenocytes require MerTK transmission of intracellular signaling to suppress the production of inflammatory cytokine interferon α (IFN-α). We further demonstrate that MerTK is crucial for subsequent expansion of myeloid-derived suppressor cells and for promoting their immunomodulatory function, including maintaining graft-infiltrating CD4 CD25 Foxp3 regulatory T cells. Consequently, recipient MerTK deficiency resulted in failure of tolerance by donor apoptotic cells, and this failure could be effectively rescued by IFN-α receptor blockade. These findings underscore the importance of the efferocytic receptor MerTK in mediating transplantation tolerance by donor apoptotic cells and implicate MerTK agonism as a promising target for promoting transplantation tolerance.

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Section: Reciprocally We Tested Whether Graft Protection By Donor Ecmentioning

confidence: 99%

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Zhang

DeBerge

Wang

et al. 2019

American Journal of Transplantation

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“…It is clear that, despite their common biological function, PS receptors are disparate in their structural arrangement and sequence homology across member. PS receptors often are regulated by different transcriptional and post‐translational mechanisms, and in many cases have unique expression patterns that add complexity to their biology …”

Section: Ps/ps‐receptor Interactions and The Regulation Of Efferocytomentioning

confidence: 99%

“…PS receptors often are regulated by different transcriptional and post-translational mechanisms, and in many cases have unique expression patterns that add complexity to their biology. 83 Finally, in addition to receptors or soluble proteins alluded to above that recognize PS when presented as an external signal, several scavenger receptors can broadly recognize the negative charge PS, adding both diversity and complexity to PS receptor signaling and function. 45 For example, CD36, CD91 (also called LDL-receptor related protein; LRP, the homolog of CED1) and CD68 have been implicated in the recognition and clearance of apoptotic cells, although as noted above, these receptors likely also recognize additional chemical modalities on the apoptotic cells, such as modified carbohydrates, acetylated components of the glycocalyx, and altered sialic acid residues (socalled apoptotic cell associated molecular patterns or ACAMPs).…”

Section: Ps/ps-receptor Interactions and The Regulation Of Efferocymentioning

confidence: 99%

Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment

Kumar

Calianese

Birge

2017

Immunological Reviews

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Programmed cell death (apoptosis) is an integral part of tissue homeostasis in complex organisms, allowing for tissue turnover, repair, and renewal while simultaneously inhibiting the release of self antigens and danger signals from apoptotic cell-derived constituents that can result in immune activation, inflammation, and autoimmunity. Unlike cells in culture, the physiological fate of cells that die by apoptosis in vivo is their rapid recognition and engulfment by phagocytic cells (a process called efferocytosis). To this end, apoptotic cells express specific eat-me signals, such as externalized phosphatidylserine (PS), that are recognized in a specific context by receptors to initiate signaling pathways for engulfment. The importance of carefully regulated recognition and clearance pathways is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in PS receptors and signaling molecules. However, in recent years, several additional cell death pathways have emerged, including immunogenic cell death, necroptosis, pyroptosis, and netosis that interweave different cell death pathways with distinct innate and adaptive responses from classical apoptosis that can shape long-term host immunity. In this review, we discuss the role of different cell death pathways in terms of their immune potential outcomes specifically resulting in specific cell corpse/phagocyte interactions (phagocytic synapses) that impinge on host immunity, with a main emphasis on tolerance and cancer immunotherapy.

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“…This finding was followed by observational studies reporting 20–30% reductions in prostate cancer risk with VKA use as well as studies reporting neutral associations . In laboratory studies, VKAs have been demonstrated to inhibit Axl–receptor signaling involved in cell growth regulation and to reduce transcriptional activity of the androgen receptor in prostate cancer cells …”

Section: Introductionmentioning

confidence: 95%

“…[8][9][10] In laboratory studies, VKAs have been demonstrated to inhibit Axlreceptor signaling involved in cell growth regulation and to reduce transcriptional activity of the androgen receptor in prostate cancer cells. 11,12 Given the conflicting epidemiological findings and the potential implications for development of drugs for prevention or treatment of prostate cancer, we conducted a systematic review of the literature, examined the association between VKA use and prostate cancer risk in a nationwide nested case-control study, and pooled the risk estimates from previous and the present study in a meta-analysis.…”

Section: Introductionmentioning

confidence: 99%

Use of vitamin K antagonists and risk of prostate cancer: Meta–analysis and nationwide case–control study

Kristensen

Jensen

Skriver

et al. 2018

Intl Journal of Cancer

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Use of vitamin K antagonists (VKAs) has been suggested to reduce the risk of prostate cancer. We conducted a nested case–control study using Danish demographic and health data registries and summarized existing evidence in a meta‐analysis. The case–control study included all Danish men aged 40–85 years with incident histologically verified prostate adenocarcinoma between 2005 and 2015 (cases). For each case, we selected 10 age–matched controls. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CI) for prostate cancer associated with long–term VKA use adjusted for concomitant drug use, medical history and socioeconomic status. Among 38,832 prostate cancer cases, 1,089 (2.8%) had used VKAs for 3 or more years compared to 10,803 (2.8%) controls yielding a crude OR of 1.01 (95% CI, 0.95–1.08). Multivariable adjustment for covariates had limited influence on the association (OR, 1.03; 95% CI, 0.97–1.10). We observed no dose–response relationship (e.g. OR for 5–10 years of use, 1.06 95% CI, 0.97–1.16). We included 8 studies in the meta–analysis reporting effect estimates from 0.51 (95% CI, 0.23–1.13) to 1.10 (95% CI, 0.94–1.40). Using random effect methods, a pooled effect estimate of 0.86 (95% CI, 0.70–1.05) was obtained; however, there was considerable across–study heterogeneity (I2: 93.9%). In conclusion, we did not observe a reduced risk of prostate cancer associated with VKA use in this nationwide study and, taken together with previous study findings, a major protective effect of VKAs against prostate cancer seems unlikely.

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Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response

Cited by 61 publications

References 105 publications

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Receptor tyrosine kinase MerTK suppresses an allogenic type I IFN response to promote transplant tolerance

Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment

Use of vitamin K antagonists and risk of prostate cancer: Meta–analysis and nationwide case–control study

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