AI
Friday, February 10, 2017 12:45:16 PM
2-9-17/AACR Article: R.Birge+PPHM, “PS Sensing by TAM Receptors Regulates AKT-dependent Chemoresistance & PD-L1 Expression”. Lead author, Rutgers' Dr. Raymond Birge. Also, 2 co-authors from Advanced Proteome Therapeutics, in addition to PPHM scientists.
2-9-17/AACR: “Phosphatidylserine Sensing by TAM Receptors Regulates AKT-dependent Chemoresistance and PD-L1 Expression”
Rec. 10-27-16, rev. 12-30-16, Acc 1-13-17, PUB. 2-9-17
*RUTGERS: Canan Kasikara, Sushil Kumar, Stanley Kimani, Wen-I Tsou, Ke Geng, Viralkumar Davra, Ganapathy Sriram, Connor Devoe, Khanh-Quynh Nguyen, Anita Antes, Sergei V Kotenko, Raymond B. Birge [Lead Author http://birgelab.org ]
*ADVANCED PROTEOME THERAPEUTICS: Allen Krantz, Andrzej Wilczynski http://advancedproteome.com
*BOSTON UNIV: Grzegorz Rymarczyk
*PEREGRINE: Cyril Empig, Bruce D Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins
http://mcr.aacrjournals.org/content/early/2017/02/09/1541-7786.MCR-16-0350
https://www.ncbi.nlm.nih.gov/pubmed/28184013
ABSTRACT:
Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases (RTKs) that bind vitamin K-dependent endogenous ligands, Protein S (ProS) and Growth arrest specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radio-resistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment (TME) that can suppress host anti-tumor immunity. In the present study, we utilized TAM-IFNgammaR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express WT TAM receptors, and show that while each receptor can promote PS-mediated efferocytosis, AKT-mediated chemo-resistance, as well as up-regulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor-mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 [***] and Annexin V, demonstrating the existing of a PS/PS-Receptor (i.e. TAM-receptor) /PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti-TAM receptor, and anti-PD-L1 based therapeutics will have merit as combinatorial checkpoint inhibitors. Implications: Many tumor cells are known to up-regulate the immune checkpoint inhibitor PD-L1. This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on breast cancers cells.
---------
[***NOTE: Mab 11.31 is PGN632 (B2GPI-indep.), the Duke-PPHM-HIV candidate=11.31=AT005; also being studied by PPHM+LSU vs. Ocular Herpes (Acute HSV-1 Keratitis), see http://tinyurl.com/cax9a4p ]
= = = = = = = = = = = = = = = = = = = =
Interesting that one Birge/Rutgers Lab Member’s Theme/Mission is, “Regulation of Phosphatidylserine (PS) Externalization in the Tumor Micro-Environment; Role of PS as an Immunosuppressive Signal”. http://birgelab.org/lab.html
Raymond Birge, PhD - Univ. of Connecticut, Post-doc: Rockefeller Univ.
“Cancer Metastasis and Immune Evasion”
...Dr. Raymond Birge has authored ~85 scientific publications in molecular & cancer biology. http://www.ncbi.nlm.nih.gov/pubmed/?term=birge+rb
http://birgelab.org => http://birgelab.org/biography.html
“The Birge laboratory conducts basic science focused on the eradication of cancer.”
Ke Geng - BS: Zhengzhou Univ. Medical School
“Regulation of Phosphatidylserine (PS) Externalization in the Tumor Micro-Environment; Role of PS as an Immunosuppressive Signal”
= = = = = = = = = = = = = = = = = = ==
2-2016: Rutgers' Dr. Raymond Birge's relationship with Peregrine & UTSW's Dr. Rolf Brekken and his 2-26-16 article, ”Phosphatidylserine is a Global Immunosuppressive Signal in Efferocytosis, Infectious Disease, and Cancer” http://tinyurl.com/z5d9qt9
11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
2-9-17/AACR: “Phosphatidylserine Sensing by TAM Receptors Regulates AKT-dependent Chemoresistance and PD-L1 Expression”
Rec. 10-27-16, rev. 12-30-16, Acc 1-13-17, PUB. 2-9-17
*RUTGERS: Canan Kasikara, Sushil Kumar, Stanley Kimani, Wen-I Tsou, Ke Geng, Viralkumar Davra, Ganapathy Sriram, Connor Devoe, Khanh-Quynh Nguyen, Anita Antes, Sergei V Kotenko, Raymond B. Birge [Lead Author http://birgelab.org ]
*ADVANCED PROTEOME THERAPEUTICS: Allen Krantz, Andrzej Wilczynski http://advancedproteome.com
*BOSTON UNIV: Grzegorz Rymarczyk
*PEREGRINE: Cyril Empig, Bruce D Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins
http://mcr.aacrjournals.org/content/early/2017/02/09/1541-7786.MCR-16-0350
https://www.ncbi.nlm.nih.gov/pubmed/28184013
ABSTRACT:
Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases (RTKs) that bind vitamin K-dependent endogenous ligands, Protein S (ProS) and Growth arrest specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radio-resistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment (TME) that can suppress host anti-tumor immunity. In the present study, we utilized TAM-IFNgammaR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express WT TAM receptors, and show that while each receptor can promote PS-mediated efferocytosis, AKT-mediated chemo-resistance, as well as up-regulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor-mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 [***] and Annexin V, demonstrating the existing of a PS/PS-Receptor (i.e. TAM-receptor) /PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti-TAM receptor, and anti-PD-L1 based therapeutics will have merit as combinatorial checkpoint inhibitors. Implications: Many tumor cells are known to up-regulate the immune checkpoint inhibitor PD-L1. This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on breast cancers cells.
---------
[***NOTE: Mab 11.31 is PGN632 (B2GPI-indep.), the Duke-PPHM-HIV candidate=11.31=AT005; also being studied by PPHM+LSU vs. Ocular Herpes (Acute HSV-1 Keratitis), see http://tinyurl.com/cax9a4p ]
= = = = = = = = = = = = = = = = = = = =
Interesting that one Birge/Rutgers Lab Member’s Theme/Mission is, “Regulation of Phosphatidylserine (PS) Externalization in the Tumor Micro-Environment; Role of PS as an Immunosuppressive Signal”. http://birgelab.org/lab.html
Raymond Birge, PhD - Univ. of Connecticut, Post-doc: Rockefeller Univ.
“Cancer Metastasis and Immune Evasion”
...Dr. Raymond Birge has authored ~85 scientific publications in molecular & cancer biology. http://www.ncbi.nlm.nih.gov/pubmed/?term=birge+rb
http://birgelab.org => http://birgelab.org/biography.html
“The Birge laboratory conducts basic science focused on the eradication of cancer.”
Ke Geng - BS: Zhengzhou Univ. Medical School
“Regulation of Phosphatidylserine (PS) Externalization in the Tumor Micro-Environment; Role of PS as an Immunosuppressive Signal”
= = = = = = = = = = = = = = = = = = ==
2-2016: Rutgers' Dr. Raymond Birge's relationship with Peregrine & UTSW's Dr. Rolf Brekken and his 2-26-16 article, ”Phosphatidylserine is a Global Immunosuppressive Signal in Efferocytosis, Infectious Disease, and Cancer” http://tinyurl.com/z5d9qt9
11-9-15 SITC'15: New Bavi+Checkpoint Inhibitors preclin. data (UTSW/DUKE's Herbert K. Lyerly) http://tinyurl.com/pbof95w
...Also, collab. with Dr. Bernard Fox (Immunotherapist/Earle A. Chiles Res.Inst.) on new Immuno-Profiling Clinical Test (Opal 6-plex quantitative IF Assay), PPHM roundtable with Raymond Birge (Rutgers), Douglas Graham (Emory), Dmitry Gabrilovich (Wistar), Rolf Brekken (UTSW), Maria Karasarides (AstraZeneca) - ”Combining Bavi w/anti-PD-1 significantly enhanced O/S… significant incr. CD45+, CD8+ and CD3+ T-cells… led a prolonged anti-tumor immune response which protected the animals against a re-challenge w/same tumor.”
