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Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity.


ABSTRACT: Fc?Rs are critical mediators of mAb cancer therapies, because they drive cytotoxic processes upon binding of effector cells to opsonized targets. Along with NK cells, monocytes are also known to destroy Ab-coated targets via Ab-dependent cellular cytotoxicity (ADCC). However, the precise mechanisms by which monocytes carry out this function have remained elusive. In this article, we show that human monocytes produce the protease granzyme B upon both Fc?R and TLR8 activation. Treatment with TLR8 agonists elicited granzyme B and also enhanced Fc?R-mediated granzyme B production in an additive fashion. Furthermore, monocyte-mediated ADCC against cetuximab-coated tumor targets was enhanced by TLR8 agonist treatment, and this enhancement of ADCC required granzyme B. Hence we have identified granzyme B as an important mediator of Fc?R function in human monocytes and have uncovered another mechanism by which TLR8 agonists may enhance Fc?R-based therapies.

SUBMITTER: Elavazhagan S 

PROVIDER: S-EPMC4355383 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity.

Elavazhagan Saranya S   Fatehchand Kavin K   Santhanam Vikram V   Fang Huiqing H   Ren Li L   Gautam Shalini S   Reader Brenda B   Mo Xiaokui X   Cheney Carolyn C   Briercheck Edward E   Vasilakos John P JP   Dietsch Gregory N GN   Hershberg Robert M RM   Caligiuri Michael M   Byrd John C JC   Butchar Jonathan P JP   Tridandapani Susheela S  

Journal of immunology (Baltimore, Md. : 1950) 20150209 6


FcγRs are critical mediators of mAb cancer therapies, because they drive cytotoxic processes upon binding of effector cells to opsonized targets. Along with NK cells, monocytes are also known to destroy Ab-coated targets via Ab-dependent cellular cytotoxicity (ADCC). However, the precise mechanisms by which monocytes carry out this function have remained elusive. In this article, we show that human monocytes produce the protease granzyme B upon both FcγR and TLR8 activation. Treatment with TLR8  ...[more]

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