PMID- 27129972 OWN - NLM STAT- MEDLINE DCOM- 20170206 LR - 20240427 IS - 1432-0851 (Electronic) IS - 0340-7004 (Print) IS - 0340-7004 (Linking) VI - 65 IP - 6 DP - 2016 Jun TI - Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells. PG - 741-51 LID - 10.1007/s00262-016-1841-6 [doi] AB - Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen-processing machinery proteins TAP1, LMP2, and calnexin does not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather, it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV-LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response. FAU - Chawla, Akhil AU - Chawla A AD - Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Alatrash, Gheath AU - Alatrash G AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. galatras@mdanderson.org. FAU - Philips, Anne V AU - Philips AV AD - Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Qiao, Na AU - Qiao N AD - Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Sukhumalchandra, Pariya AU - Sukhumalchandra P AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. FAU - Kerros, Celine AU - Kerros C AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. FAU - Diaconu, Iulia AU - Diaconu I AD - Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. FAU - Gall, Victor AU - Gall V AD - Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Neal, Samantha AU - Neal S AD - Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Peters, Haley L AU - Peters HL AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. FAU - Clise-Dwyer, Karen AU - Clise-Dwyer K AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. FAU - Molldrem, Jeffrey J AU - Molldrem JJ AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0900, Houston, TX, 77030, USA. FAU - Mittendorf, Elizabeth A AU - Mittendorf EA AD - Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. eamitten@mdanderson.org. AD - Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1434, Houston, TX, 77030, USA. eamitten@mdanderson.org. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R00 CA133244/CA/NCI NIH HHS/United States GR - T32 CA009598/CA/NCI NIH HHS/United States GR - P50 CA100632/CA/NCI NIH HHS/United States GR - P01 CA148600/CA/NCI NIH HHS/United States GR - T32 CA009599/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20160429 PL - Germany TA - Cancer Immunol Immunother JT - Cancer immunology, immunotherapy : CII JID - 8605732 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Peptides) RN - EC 3.4.21.37 (Leukocyte Elastase) SB - IM MH - Antigen Presentation/*immunology MH - Cell Line, Tumor MH - Cytotoxicity, Immunologic MH - *Gene Expression Regulation MH - Histocompatibility Antigens Class I/*genetics/immunology MH - Humans MH - Leukocyte Elastase/*metabolism MH - Neoplasms/*genetics/*immunology/*metabolism MH - Peptides/immunology MH - T-Lymphocytes, Cytotoxic/immunology/metabolism PMC - PMC5764112 MID - NIHMS907667 OTO - NOTNLM OT - Adaptive immunity OT - Breast cancer OT - HLA class I OT - Neutrophil elastase OT - Tumor-associated neutrophils COIS- The authors have no conflict of interest. EDAT- 2016/05/01 06:00 MHDA- 2017/02/07 06:00 PMCR- 2016/04/29 CRDT- 2016/05/01 06:00 PHST- 2015/04/14 00:00 [received] PHST- 2016/04/09 00:00 [accepted] PHST- 2016/05/01 06:00 [entrez] PHST- 2016/05/01 06:00 [pubmed] PHST- 2017/02/07 06:00 [medline] PHST- 2016/04/29 00:00 [pmc-release] AID - 10.1007/s00262-016-1841-6 [pii] AID - 1841 [pii] AID - 10.1007/s00262-016-1841-6 [doi] PST - ppublish SO - Cancer Immunol Immunother. 2016 Jun;65(6):741-51. doi: 10.1007/s00262-016-1841-6. Epub 2016 Apr 29.