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Cytotoxic T-Lymphocyte Response to Autologous Human Squamous Cell Cancer of the Lung: Epitope Reconstitution with Peptides Extracted from HLA-Aw68'

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Cytotoxic T-Lymphocyte Response to Autologous Human Squamous Cell Cancer of the Lung: Epitope Reconstitution with Peptides Extracted from HLA-Aw68' [CANCER RESEARCH 54, 2731—2737,May 15, 1994) Cytotoxic T-Lymphocyte Response to Autologous Human Squamous Cell Cancer of the Lung: Epitope Reconstitution with Peptides Extracted from HLA-Aw68' Craig L Slingluff, Jr.,2 Andrea L Cox, John M. Stover, Jr., Marcia M. Moore, Donald F. Hunt, and Victor H. Engeihard Departments ofSurgery (C. L S., J. M. S., M. M. MI, Chemistrj [A. L. C., D. F. H.J, and Mkrobiology [V. H. E.J, University of Virginia, Charlottesville, Virginia 22908 ABSTRACT associated peptides, MHC-unrestricted tumor-specific CTLs have also been described (ii, 12): the peptide backbone of a mucin Cytotoxic T-lymphocytes (Cfls) specific for autologous human squa molecule appears to be the target for some CTLs specific for mom cell cancer of the lung were generated by stimulation of peripheral blood lymphocytes with autologous tumor cells in vitro. The Cl@Lline was carcinomas of the pancreas and of the breast. It is believed that >97% @1J3+,CD8@,CD16andproducedtumornecrosisfactor-a,y-in identification of the peptide epitopes for tumor-specific CTLs will terferon, and granulocyte-macrophage colony-stimulating factor after impact our understanding of the host:tumor relationship and may stimulation with autologous tumor. The CTLs lysed autologous tumor but permit the rational development of novel immunotherapeutic strat failed to recognize autologous or histocompatability leukocyte antigen egies to treat patients with cancer. Although there is evidence of an matched lymphoid cells, K562, or allogeneic tumor cells of several histo immune response to lung cancer, little is known about the target logical types. Antibody-blocking studies suggested that the CTLs re antigens for lung cancer-specific CTLs. cognized one or more antigens presented by the class I major histocom patibility complex molecule Aw68. To Characterize these antigens f@irtber, In situ evidence for a cellular immune response to lung cancers has histocompatablilty leukocyte antigen Aw68 molecules were extracted from been suggested by electron microscopy of human lung cancers, in the squamous cell cancer of the lung tumor line by immunoaffinity cluding squamous cell cancers (13), in which tumor-infiltrating bym chromatography, and the associated peptides were eluted In acid and phocytes exhibited morphological evidence of activation and neigh separated by reversed-phase high-performance liquid chromatography. boring tumor cells were damaged or destroyed. Laboratory Reconstitution ofthe CTL epitope was evaluated by adding these peptides investigation of the cellular immune response to lung cancers has been to autologous Epstein-Barr vinis-transformed B-cells. Two peaks of re constituting activity were observed, suggesting that these Cl'Ls recognize ongoing for at least 2 decades. Much of the early work focused on atleast two Aw68-associated peptides. This study confirms the existence of proliferative and cytotoxic responses of fresh lymphocytes, which a CTL response against autologous human squamous cell cancer of the suggested some reactivity against autobogous lung cancers (14). Gen lung and suggests that this CFL response is directed against peptide eration and characterization of tumor-specific CFL lines was de epitopes presented by the class I matjor histocompatibifity complex mole scribed in 1982 by Vose and Bonnard (15, 16); several of the CTL eWes. It is anticipated that this approach will permit identification of lines were specific for autologous SCCL. Each lysed autobogous peptide epitopes for lung cancer-specific CTLs tumor, failed to lyse K562 or autobogous normal cells, and, with rare exceptions, failed to lyse allogeneic tumors. The nature ofthe epitopes INTRODUCJION for these crLs was not elucidated, and the role of MHC molecules Tumor-specific CTLs@have been generated in vitro from patients was not specifically addressed. Other investigators studied 7-day with many different solid tumors. Among these, the Cli response IL-2-stimulated mixed lymphocyte tumor cultures from patients with to melanoma has been described in the greatest detail. In the lung cancers of unspecified histological type (17). Even at this early majority of cases, the effector cells are CD3@, CD8@, CD4, time, some of the resultant lines lysed autobogous tumor better than CD16, and T-cell receptor-a/p (1—4),and the recognition of ailogeneic tumor, and antibody-blocking studies suggested a role for target cells is restricted by class I MHC molecules (5, 6). The CD8@ cells in autobogous tumor lysis. Kurnick et aL, Kradin et al., specific MHC molecules involved have been identified in many and others have generated tumor-infiltrating lymphocyte cultures cases, the best-defined of which is HLA-A2.1 (6—9).The HLA from adenocarcinomas of the lung (18) and have used such cultures A2. 1 molecule presents at least six shared peptides that function as for adoptive immunotherapy (19) with modest responses in a majority epitopes for melanoma-specific CTL (9). Several Al-associated of patients. Autobogous tumor lysis was demonstrated in a minority of CTL epitopes exist, and one HLA-A1-associated melanoma pep these cases, tumor specificity was not demonstrated, and the nature of tide has been sequenced (10). Despite the expectation that CTL the CTL epitopes was not evaluated. responses to other tumors would also be directed against MHC In summary, there is substantial evidence of a cellular immune response to human lung cancers in general and to SCCLS in particular, Received 10/1/93; accepted 3/14/94. Thecostsof publicationofthisarticleweredefrayedinpartby thepaymentofpage and there is some evidence that the immune response may have charges. This article must therefore be hereby marked advertisement in accordance with clinical significance and therapeutic potential. The development of 18 U.S.C. Section 1734 solely to indicate this fact. immunotherapy for SCCL will depend on a more detailed understand 1 This work is supported in part by the Cancer Center Grant NIH P30CA44579 (to C. L S. and V. H. E.) at the University of Virginia, by American Cancer Society Grant ing of the host:tumor response and on the identification of specific 1N149H (to C. L S.), by NIH Grants A120963 (to V. H. B.) and GM37537 (to D. F. H.), epitopes for SCCL-specific CTLs. Initially, it is necessary to define andby theDiabetesCenter(NIHP30DK38942)attheUniversityofVirginia. 2 To whom requests for reprints should be addressed, at Department of Surgery, Box the nature of the CFL epitopes for SCCL-specific CTLs. Subse 3111-MR4,UniversityofVirginiaHealthSciencesCenter,Charlottesville,VA22908. quently, identification of shared antigens and specific characterization 3 The abbreviations used are: Cli, cytotoxic T-lymphocyte; MHC, major histocom patibility complex; HLA, histocompatabifity leukocyte antigen; SCCL, squamous cell of those antigens may permit the rational development of novel carcinoma of the lung; IL-2 interleukin 2; rIL-2, recombinant interleukin 2; MEM, immunotherapy. The goal of the present report is to address the initial minimal essential media; F@S,fetal calf serum; pen/strept, 100 Units/mIpenicillin and 100 @g/mlstreptomycin;EBV, Epstein-Barr virus; PHA, phytohemagglutinin antigen; issue of the nature of the CTL epitopes. We will describe restriction TLR, tumor to lymphocyte ratio; TNF, tumor necrosis factor-a; ‘y-IFN,y-interferon; of SCCL-specific CTLs by class I MHC molecules,will define a GM-tSF, granuincyte-macrophage colony-stimulating factor, EUSA, enzyme-linked specific restricting antigen, and will document the existence of at beast immunosorbent assay; HPLC, high-performance liquid chromatography; VBT2-EBV, EBV-transformed B-cells; E:T, effectortarget ratio. two MHC-associated peptides as epitopes for these CTLs. 273i Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1994 American Association for Cancer Research. 1-CELL RESPONSE TO LUNG CANCER Table 1 Human cell lines used in this study: HL4 types linederivedThelungcancersVBT2andSk-Mes-1aresquamouscellcarcinomas.5k-Lu-iandthebreast,colon,andovariancancersareadenocarcinomas.VBT2-EBVisan EBV-B-cell lymphocytes.Thefrom VBT2 PBL and autologous to VBT2 tumor. HLA typing of VBT2, VMM1, and VMM5 was performed by microcytotoxicity assay (Gentrak) on autologous othercellexpression of HLA-Aw68 on tumor cells was confirmed by specific antibody staining of the tumor cells with the monoclonal antibody CRI1—351(26). HLA types of the lineshavebeenreported(6,9,41—43).Cell 21,22, -DOVBT2line (ref) Cell type FLLA-A -B -C HLA-DR 4CALU-1 Lung cancer, squamous 34, 68 35 —Sk-Mes-l(41) Lungcancer,epidermoid 10,11 15,35 — — —5k-Lu-i(41) Lungcancer,squamous 3, 30 7, 27 — — —DM6(41) Lung cancer, adenocarcinoma 24, 32 27, 41 — — (7?)―DM13(6, 9) Melanoma 2.1 12,13,or 35 1,2 6, 10, NDDM14(6, 9) Melanoma 2.1, 31 13, 18 @.4J)C ND (6) Melanoma 11,28 5, 8 2, 4 — — DM936bSkMel24 (6, 9) Melanoma 2.1, 33 8, 49 ND 2, 4, —HT144(9, 41) Melanoma 1, 2.1 12, 14 — — —1ff144(41) Melanoma 1, 24 13, 15 3 4, 7 —VMM1A2-03 Melanoma 1, 2.1, 24 13, 15 3 4, 7 —VMM5(9) Melanoma 3, 26 51, w4, w6 ND — 7VMM1(9) Melanoma 2.1 39 ND 7, 11, 52, 53 2, —MDAMB4681 Melanoma 30, 34 18 — — —CCL228(41)(41) Breast cancer 23, 30 27, 35 2, 4 — —143b Coloncancer 2.1 8,17 — — —GM126(42) Osteosarcoma 2.1 — — — —K562 (42) Fibroblasts 2.1 — — — —C1R-Aw68 Erythroleukemia — — — — (w3)JY (21, 22) EBV-B 68 — 4 5 (w12), 52 w7 —Herluff(44) EBV-B 2.1,2.1 7, 7 — 4, 6 (9) EBV-B 2.1, 2.1 12, 35 — — — a none reportedor not evaluated. Th@ DR antigensare listed becausecross-reactivitypreventedascertainingwith certaintywhich two were correct. C ND, none detected, either by microcytotoxicity assay or by staining with monoclonal antibodies.
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