TY - JOUR
T1 - Granzyme B expression is enhanced in human monocytes by TLR8 agonists and contributes to antibody-dependent cellular cytotoxicity
AU - Elavazhagan, Saranya
AU - Fatehchand, Kavin
AU - Santhanam, Vikram
AU - Fang, Huiqing
AU - Ren, Li
AU - Gautam, Shalini
AU - Reader, Brenda
AU - Mo, Xiaokui
AU - Cheney, Carolyn
AU - Briercheck, Edward
AU - Vasilakos, John P.
AU - Dietsch, Gregory N.
AU - Hershberg, Robert M.
AU - Caligiuri, Michael
AU - Byrd, John C.
AU - Butchar, Jonathan P.
AU - Tridandapani, Susheela
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/3/15
Y1 - 2015/3/15
N2 - FcgRs 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 FcgR and TLR8 activation. Treatment with TLR8 agonists elicited granzyme B and also enhanced FcgR-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 FcgR function in human monocytes and have uncovered another mechanism by which TLR8 agonists may enhance FcgR-based therapies.
AB - FcgRs 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 FcgR and TLR8 activation. Treatment with TLR8 agonists elicited granzyme B and also enhanced FcgR-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 FcgR function in human monocytes and have uncovered another mechanism by which TLR8 agonists may enhance FcgR-based therapies.
UR - https://www.scopus.com/pages/publications/84924546707
U2 - 10.4049/jimmunol.1402316
DO - 10.4049/jimmunol.1402316
M3 - Article
C2 - 25667415
AN - SCOPUS:84924546707
SN - 0022-1767
VL - 194
SP - 2786
EP - 2795
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -