Biopolym. Cell. 2021; 37(2):105-116.
http://dx.doi.org/10.7124/bc.000A50
Molecular Biomedicine
Somatic genomic rearrangements in human leucocyte antigens region in solid ovarian tumors
1Hryshchenko N. V., 1Gordiyuk V. V., 1Kravchenko S. A., 2Arbuzova S. B., 1Kashuba V. I.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  2. Municipal Nonprofit Enterprise East-Ukrainian Specialized Center Of Medical Genetics and Prenatal Diagnosis
    35 Nakhimov av., Mariupol, Ukraine, 87517
  3. Karolinska Institutet
    Stockholm SE-171 77, Sweden

Abstract

The success of immunotherapy for ovarian cancer is determined by the effectiveness of the patient’s immune response, as well as the qualitative and quantitative representation of antigens of the main histocompatibility complex in tumor cells and microenvironment. The level of the HLA (Human Leukocyte Antigens) genes expression in tumor tissue does not always correctly reflect the expression of these genes in different populations of tumor cells. Aim. To analyze the frequency and range of somatic deletions and duplications in the HLA locus. Methods. LOH-analysis (Loss of Heterozyhosity) of the STR-markers (Short Tandem Repeats) in the ovarian tumors of affected patients. Results. We have shown that complex somatic genomic reorganizations, involving several HLA loci, are quite common in ovarian tumors. The detected genetic alterations vary by both the type (deletions and mutations in STR alleles) and proportion of the sub-population of cells with the alterations. Conclusions. The results obtained allow us to propose the LOH-analysis for highly effective detection of aneuploidy and different types of somatic genomic reorganizations in the HLA region even in minor cell populations. This analysis provides the additional prognostic information for predicting the effectiveness of different types of ovarian cancer immunotherapy at the individual level.
Keywords: ovarian cancer, immune response, STR-marker, HLA, genetic alteration
Full text: (PDF, in English)

References

[1] Suh DH, Kim M, Lee KH, Eom KY, Kjeldsen MK, Mirza MR, Kim JW. Major clinical research advances in gynecologic cancer in 2017. J Gynecol Oncol. 2018;29(2):e31.
[2] Liu XS, Mardis ER. Applications of Immunogenomics to Cancer. Cell. 2017;168(4):600-612.
[3] Flores-Villanueva PO, Ganachari M, Guio H, Mejia JA, Granados J. An Isolated TCR αβ Restricted by HLA-A*02:01/CT37 Peptide Redirecting CD8+ T Cells To Kill and Secrete IFN-γ in Response to Lung Adenocarcinoma Cell Lines. J Immunol. 2018;200(8):2965-2977.
[4] Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode EL, Block MS, Kalli KR, Vierkant RA, Chen W, Fogarty ZC, Gentry-Maharaj A, Tołoczko A, Hein A, Bouligny AL, Jensen A, Osorio A, Hartkopf A, Ryan A, Chudecka-Głaz A, Magliocco AM, Hartmann A, Jung AY, Gao B, Hernandez BY, Fridley BL, McCauley BM, Kennedy CJ, Wang C, Karpinskyj C, de Sousa CB, Tiezzi DG, Wachter DL, Herpel E, Taran FA, Modugno F, Nelson G, Lubiński J, Menkiszak J, Alsop J, Lester J, García-Donas J, Nation J, Hung J, Palacios J, Rothstein JH, Kelley JL, de Andrade JM, Robles-Díaz L, Intermaggio MP, Widschwendter M, Beckmann MW, Ruebner M, Jimenez-Linan M, Singh N, Oszurek O, Harnett PR, Rambau PF, Sinn P, Wagner P, Ghatage P, Sharma R, Edwards RP, Ness RB, Orsulic S, Brucker SY, Johnatty SE, Longacre TA, Ursula E, McGuire V, Sieh W, Natanzon Y, Li Z, Whittemore AS, Anna A, Staebler A, Karlan BY, Gilks B, Bowtell DD, Høgdall E, Candido dos Reis FJ, Steed H, Campbell IG, Gronwald J, Benítez J, Koziak JM, Chang-Claude J, Moysich KB, Kelemen LE, Cook LS, Goodman MT, García MJ, Fasching PA, Kommoss S, Deen S, Kjaer SK, Menon U, Brenton JD, Pharoah PDP, Chenevix-Trench G, Huntsman DG, Winham SJ, Köbel M, Ramus SJ. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncol. 2017;3(12):e173290.
[5] Santoiemma PP, Powell DJ Jr. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol Ther. 2015;16(6):807-20.
[6] Abelin JG, Harjanto D, Malloy M, Suri P, Colson T, Goulding SP, Creech AL, Serrano LR, Nasir G, Nasrullah Y, McGann CD, Velez D, Ting YS, Poran A, Rothenberg DA, Chhangawala S, Rubinsteyn A, Hammerbacher J, Gaynor RB, Fritsch EF, Greshock J, Oslund RC, Barthelme D, Addona TA, Arieta CM, Rooney MS. Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction. Immunity. 2019;51(4):766-779.e17.
[7] Smith HA, Rekoske BT, McNeel DG. DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses. Vaccine. 2014;32(15):1707-15.
[8] Boettcher AN, Usman A, Morgans A, VanderWeele DJ, Sosman J, Wu JD. Past, Current, and Future of Immunotherapies for Prostate Cancer. Front Oncol. 2019;9:884.
[9] Gálvez-Cancino F, López E, Menares E, Díaz X, Flores C, Cáceres P, Hidalgo S, Chovar O, Alcántara-Hernández M, Borgna V, Varas-Godoy M, Salazar-Onfray F, Idoyaga J, Lladser A. Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma. Oncoimmunology. 2018;7(7):e1442163.
[10] Neumann A, Hörzer H, Hillen N, Klingel K, Schmid-Horch B, Bühring HJ, Rammensee HG, Aebert H, Stevanović S. Identification of HLA ligands and T-cell epitopes for immunotherapy of lung cancer. Cancer Immunol Immunother. 2013;62(9):1485-97.
[11] Seliger B, Stoehr R, Handke D, Mueller A, Ferrone S, Wullich B, Tannapfel A, Hofstaedter F, Hartmann A. Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer. Cancer Immunol Immunother. 2010;59(4):529-40.
[12] Ottenhof SR, Djajadiningrat RS, Thygesen HH, Jakobs PJ, Jóźwiak K, Heeren AM, de Jong J, Sanders J, Horenblas S, Jordanova ES. The Prognostic Value of Immune Factors in the Tumor Microenvironment of Penile Squamous Cell Carcinoma. Front Immunol. 2018;9:1253.
[13] Bosch JJ, Thompson JA, Srivastava MK, Iheagwara UK, Murray TG, Lotem M, Ksander BR, Ostrand-Rosenberg S. MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4(+) T lymphocytes that cross-react with primary and metastatic uveal melanoma cells. Cancer Res. 2007;67(9):4499-506.
[14] Garrido F. HLA Class-II Expression in Human Tumors. Adv Exp Med Biol. 2019;1151:91-95.
[15] Accolla RS, Ramia E, Tedeschi A, Forlani G. CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine. Front Immunol. 2019;10:1806.
[16] Doonan BP, Haque A. Prostate Cancer Immunotherapy: Exploiting the HLA Class II Pathway in Vaccine Design. J Clin Cell Immunol. 2015;6(4):351.
[17] Dalerba P, Kalisky T, Sahoo D, Rajendran PS, Rothenberg ME, Leyrat AA, Sim S, Okamoto J, Johnston DM, Qian D, Zabala M, Bueno J, Neff NF, Wang J, Shelton AA, Visser B, Hisamori S, Shimono Y, van de Wetering M, Clevers H, Clarke MF, Quake SR. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol. 2011;29(12):1120-7.
[18] Lee MC, Lopez-Diaz FJ, Khan SY, Tariq MA, Dayn Y, Vaske CJ, Radenbaugh AJ, Kim HJ, Emerson BM, Pourmand N. Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing. Proc Natl Acad Sci U S A. 2014;111(44):E4726-35.
[19] Ding S, Chen X, Shen K. Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy. Cancer Commun (Lond). 2020;40(8):329-344.
[20] Gordiyuk VV, Gerashchenko GV, Skrypkina IYa, Symonchuk OV, Pavlova TV, Ugryn DD, Manzhura EP, Vakulenko GO, Zabarovsky ER, Rynditch AV, Kashuba VI. Identification of chromosome 3 epigenetic and genetic abnormalities and gene expression changes in ovarian cancer. Biopolym Cell. 2008; 24(4):323–32.
[21] AÅŸicioglu F, Oguz-Savran F, Ozbek U. Mutation rate at commonly used forensic STR loci: paternity testing experience. Dis Markers. 2004;20(6):313-5.
[22] Kübler K, Arndt PF, Wardelmann E, Landwehr C, Krebs D, Kuhn W, van der Ven K. Genetic alterations of HLA-class II in ovarian cancer. Int J Cancer. 2008;123(6):1350-6.
[23] Schuster H, Peper JK, Bösmüller HC, Röhle K, Backert L, Bilich T, Ney B, Löffler MW, Kowalewski DJ, Trautwein N, Rabsteyn A, Engler T, Braun S, Haen SP, Walz JS, Schmid-Horch B, Brucker SY, Wallwiener D, Kohlbacher O, Fend F, Rammensee HG, Stevanović S, Staebler A, Wagner P. The immunopeptidomic landscape of ovarian carcinomas. Proc Natl Acad Sci U S A. 2017;114(46):E9942-E9951.
[24] Andersson E, Poschke I, Villabona L, Carlson JW, Lundqvist A, Kiessling R, Seliger B, Masucci GV. Non-classical HLA-class I expression in serous ovarian carcinoma: Correlation with the HLA-genotype, tumor infiltrating immune cells and prognosis. Oncoimmunology. 2015;5(1):e1052213.
[25] Hirohashi Y, Torigoe T, Mariya T, Kochin V, Saito T, Sato N. HLA class I as a predictor of clinical prognosis and CTL infiltration as a predictor of chemosensitivity in ovarian cancer. Oncoimmunology. 2015;4(5):e1005507.
[26] Pellicciotta I, Yang CP, Goldberg GL, Shahabi S. Epothilone B enhances Class I HLA and HLA-A2 surface molecule expression in ovarian cancer cells. Gynecol Oncol. 2011;122(3):625-31.
[27] Szender JB, Eng KH, Matsuzaki J, Miliotto A, Gnjatic S, Tsuji T, Odunsi K. HLA superfamily assignment is a predictor of immune response to cancer testis antigens and survival in ovarian cancer. Gynecol Oncol. 2016;142(1):158-162.