PMID- 31555275 OWN - NLM STAT- MEDLINE DCOM- 20201008 LR - 20201008 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - TRAIL-Receptor 4 Modulates gammadelta T Cell-Cytotoxicity Toward Cancer Cells. PG - 2044 LID - 10.3389/fimmu.2019.02044 [doi] LID - 2044 AB - Acquired immune evasion is one of the mechanisms that contributes to the dismal prognosis of cancer. Recently, we observed that different gammadelta T cell subsets as well as CD8(+) alphabeta T cells infiltrate the pancreatic tissue. Interestingly, the abundance of gammadelta T cells was reported to have a positive prognostic impact on survival of cancer patients. Since gammadelta T cells utilize TNF-related apoptosis inducing ligand (TRAIL) for killing of tumor cells in addition to granzyme B and perforin, we investigated the role of the TRAIL-/TRAIL-R system in gammadelta T cell-cytotoxicity toward pancreatic ductal adenocarcinoma (PDAC) and other cancer cells. Coculture of the different cancer cells with gammadelta T cells resulted in a moderate lysis of tumor cells. The lysis of PDAC Colo357 cells was independent of TRAIL as it was not inhibited by the addition of neutralizing anti-TRAIL antibodies or TRAIL-R2-Fc fusion protein. In accordance, knockdown (KD) of death receptors TRAIL-R1 or TRAIL-R2 in Colo357 cells had no effect on gammadelta T cell-mediated cytotoxicity. However, KD of decoy receptor TRAIL-R4, which robustly enhanced TRAIL-induced apoptosis, interestingly, almost completely abolished the gammadelta T cell-mediated lysis of these tumor cells. This effect was associated with a reduced secretion of granzyme B by gammadelta T cells and enhanced PGE2 production as a result of increased expression level of synthetase cyclooxygenase (COX)-2 by TRAIL-R4-KD cells. In contrast, knockin of TRAIL-R4 decreased COX-2 expression. Importantly, reduced release of granzyme B by gammadelta T cells cocultured with TRAIL-R4-KD cells was partially reverted by bispecific antibody [HER2xCD3] and led in consequence to enhanced lysis of tumor cells. Likewise, inhibition of COX-1 and/or COX-2 partially enhanced gammadelta T cell-mediated lysis of TRAIL-R4-KD cells. The combination of bispecific antibody and COX-inhibitor completely restored the lysis of TRAIL-R4-KD cells by gammadelta T cells. In conclusion, we uncovered an unexpected novel role of TRAIL-R4 in tumor cells. In contrast to its known pro-tumoral, anti-apoptotic function, TRAIL-R4 augments the anti-tumoral cytotoxic activity of gammadelta T cells. FAU - Tawfik, Doaa AU - Tawfik D AD - Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Kiel, Germany. FAU - Groth, Christopher AU - Groth C AD - Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Kiel, Germany. AD - Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany. FAU - Gundlach, Jan-Paul AU - Gundlach JP AD - Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Kiel, Germany. AD - Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, UKSH, Campus Kiel, Kiel, Germany. FAU - Peipp, Matthias AU - Peipp M AD - Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, UKSH, CAU Kiel, Kiel, Germany. FAU - Kabelitz, Dieter AU - Kabelitz D AD - Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany. FAU - Becker, Thomas AU - Becker T AD - Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, UKSH, Campus Kiel, Kiel, Germany. FAU - Oberg, Hans-Heinrich AU - Oberg HH AD - Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany. FAU - Trauzold, Anna AU - Trauzold A AD - Institute for Experimental Cancer Research, Christian-Albrechts-University of Kiel, Kiel, Germany. AD - Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, UKSH, Campus Kiel, Kiel, Germany. FAU - Wesch, Daniela AU - Wesch D AD - Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190828 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Biomarkers) RN - 0 (Receptors, Antigen, T-Cell, gamma-delta) RN - 0 (TNFRSF10D protein, human) RN - 0 (Tumor Necrosis Factor Decoy Receptors) RN - EC 1.14.99.1 (Cyclooxygenase 1) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 1.14.99.1 (PTGS1 protein, human) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Biomarkers MH - Cell Line, Tumor MH - Cyclooxygenase 1/metabolism MH - Cyclooxygenase 2/metabolism MH - *Cytotoxicity, Immunologic MH - Dinoprostone/metabolism MH - Gene Knockdown Techniques MH - Humans MH - *Immunomodulation MH - Neoplasms/immunology/metabolism MH - Receptors, Antigen, T-Cell, gamma-delta/*metabolism MH - T-Lymphocytes/*immunology/*metabolism MH - Tumor Necrosis Factor Decoy Receptors/genetics/*metabolism PMC - PMC6722211 OTO - NOTNLM OT - COX (cyclooxygenase) OT - PGE2 OT - TRAIL OT - TRAIL-receptor 4 OT - bispecific Ab OT - granzyme B OT - pancreatic cancer OT - gammadelta T cell-cytotoxicity EDAT- 2019/09/27 06:00 MHDA- 2020/10/09 06:00 PMCR- 2019/01/01 CRDT- 2019/09/27 06:00 PHST- 2019/03/22 00:00 [received] PHST- 2019/08/13 00:00 [accepted] PHST- 2019/09/27 06:00 [entrez] PHST- 2019/09/27 06:00 [pubmed] PHST- 2020/10/09 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.02044 [doi] PST - epublish SO - Front Immunol. 2019 Aug 28;10:2044. doi: 10.3389/fimmu.2019.02044. eCollection 2019.