Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: rationale for combination therapies.
The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib has been approved for years as a first-line therapy for patients harboring EGFR-sensitizing mutations. With the promising implementation of immunotherapeutic strategies for the treatment of lung cancer, there is a growing interest in developing combinatorial therapies that could utilize immune approaches in the context of conventional or targeted therapies. Tumor cells are known to evade immune attack by multiple strategies, including undergoing phenotypic plasticity via a process designated as the epithelial-mesenchymal transition (EMT). As signaling through EGFR is a major inducer of EMT in epithelial cells, we have investigated the effect of EGFR inhibition with erlotinib on tumor phenotype and susceptibility to immune attack. Our data shows that short-term exposure of tumor cells to low-dose erlotinib modulates tumor plasticity and immune-mediated cytotoxicity in lung cancer cells harboring a sensitizing EGFR mutation, leading to a remarkable enhancement of tumor lysis mediated by innate NK cells and antigen-specific T cells. This effect positively correlated with the ability of short-term EGFR blockade to modulate tumor phenotype towards a more epithelial one, as well as to increase susceptibility to caspase-mediated apoptosis. The effect, however, was lost when erlotinib was utilized for long periods of time in vitro or in vivo, which resulted in gain of mesenchymal features and decreased (rather than increased) tumor lysis in response to immune effector mechanisms. Our data provides rationale for potential combinations of erlotinib and immunotherapies for the treatment of lung carcinomas in the early setting, before the establishment of tumor relapse with long-term EGFR inhibition.
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Charli
C
Dominguez
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Kwong-Yok
KY
Tsang
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Claudia
C
Palena
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D014408:Biomarkers, Tumor; D016209:Interleukin-8; D053218:Receptors, Death Domain; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020169:Caspases
N Engl J Med. 2015 Oct 22;373(17):1627-39
26412456
Oncoimmunology. 2013 Dec 1;2(12):e27215
24501692
Sci Transl Med. 2011 Jul 6;3(90):90ra59
21734175
Cancer Res. 2013 Apr 15;73(8):2418-27
23436798
Cancer Discov. 2015 Sep;5(9):915-9
26272491
Dev Cell. 2008 Jun;14(6):818-29
18539112
Oncoimmunology. 2012 Jan 1;1(1):71-74
22720215
Oncotarget. 2015 Apr 30;6(12):10415-31
25871388
J Immunother. 2011 May;34(4):372-81
21499124
Nat Rev Clin Oncol. 2015 Sep;12(9):511-26
25963091
Cell. 2009 Nov 25;139(5):871-90
19945376
J Clin Invest. 2009 Jun;119(6):1420-8
19487818
Oncotarget. 2013 Oct;4(10):1777-90
24125763
Cancer Res. 2006 Jan 15;66(2):944-50
16424029
Cancer Immunol Immunother. 2014 Dec;63(12):1307-17
25186612
Cancer Res. 2014 Oct 1;74(19):5572-84
25125655
Br J Cancer. 2002 Jul 1;87(1):81-5
12085261
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5746-51
11331782
Oncotarget. 2015 Sep 29;6(29):26814-25
26308162
Chin J Cancer. 2011 Oct;30(10):701-11
21959047
Cell. 2008 May 16;133(4):704-15
18485877
Future Oncol. 2012 Jun;8(6):713-22
22764769
Int Rev Cell Mol Biol. 2015;314:1-41
25619714
Int J Cancer. 2016 Jun 1;138(11):2549-61
26537995
Oncotarget. 2015 May 10;6(13):10697-711
25986923
Cancer Immunol Res. 2015 Nov;3(11):1248-56
26130065
J Natl Cancer Inst. 2012 Apr 18;104(8):599-613
22395641
J Hepatol. 2014 Aug;61(2):325-32
24704591
Cancer Biol Ther. 2015 ;16(6):933-40
25897987
Oncotarget. 2015 Mar 10;6(7):4853-62
25605015
Lancet Oncol. 2015 Jul;16(7):e342-51
26149886
World J Stem Cells. 2015 Oct 26;7(9):1185-201
26516409
Oncotarget. 2016 Jul 5;7(27):42031-42044
27248176
Ann Surg Oncol. 2013 Dec;20 Suppl 3:S509-16
23456319
Lancet Oncol. 2015 Sep;16(9):e447-59
26370354
J Clin Invest. 2010 Feb;120(2):533-44
20071775
Oncologist. 2010;15(9):969-75
20798195
Clin Cancer Res. 2013 Jan 1;19(1):279-90
23091115
Eur J Cancer. 2011 May;47(7):1080-5
21220197
Clin Cancer Res. 2012 Jul 15;18(14):3868-79
22611028
J Natl Cancer Inst. 2014 May 09;106(5):null
24815864
Cancer Res. 2005 Oct 15;65(20):9455-62
16230409
Crit Rev Immunol. 2014;34(2):91-102
24940910
Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
16493418
Cancer Res. 2014 May 1;74(9):2510-9
24626094
N Engl J Med. 2015 May 21;372(21):2018-28
25891174
Sci Transl Med. 2011 Mar 23;3(75):75ra26
21430269
Genes Dev. 2006 Jun 1;20(11):1496-510
16705038
Cancer Res. 2007 Oct 1;67(19):9066-76
17909010
Nat Rev Immunol. 2006 Oct;6(10):715-27
16977338
Stem Cells. 2009 Sep;27(9):2059-68
19544473
Cancer Res. 2010 Apr 15;70(8):3005-8
20395197
Cancer Immunol Immunother. 2014 Feb;63(2):161-74
24233342
Transl Lung Cancer Res. 2015 Oct;4(5):553-9
26629424
Autophagy. 2013 Jul;9(7):1104-6
23635487
Clin Cancer Res. 2007 Apr 15;13(8):2471-8
17438107
Expert Opin Pharmacother. 2014 Nov;15(16):2293-305
25219817
Cell Cycle. 2002 Nov-Dec;1(6):391-3
12548011
Cancer Treat Rev. 2013 Dec;39(8):839-50
23768755
Bioessays. 2001 Oct;23(10):912-23
11598958
Am J Cancer Res. 2014 Sep 06;4(5):411-35
25232485