The Adaptome as Biomarker for Assessing Cancer Immunity and Immunotherapy

  • Jian Han
  • Michael T. LotzeEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 2055)


In terms of diagnosing and treating diseases, our adaptive immune system is the “best doctor.” It carries out these tasks with unmatched precision, with the help of both T and B cell receptors, our most diverse set of genes, distinguishing one individual from another. It does this by generating autologous extraordinary diversity in the receptors, ranging from 1015 to 1025 for each chain of the rearranged receptors. By combining multiplex PCR and next-generation sequencing (NGS), we have developed high throughput methods to study adaptive immunity. The adaptome is the sum-total of expressed T and B cell receptor genes in a sample, composed of seven chains, including the alpha/beta and gamma/delta chains for T cells, and heavy/lambda or kappa chains for B cells. Immune repertoire is the sum-total of the individual clonotypes within one chain, including individual complementarity-determining regions (CDR) 3 sequences. In order to reflect the breadth and depth of the true adaptome, the following criteria assessing any method needs to be ascertained: (1) Methods need to be inclusive and quantitative; (2) Analysis should consider what questions need to be addressed and whether bulk or single cell sequencing provide the best tools for assessing the underlying biology and addressing important questions; (3) Measures of clonal diversity are key to understand the underlying structure and providence of the repertoire; and (4) Convergent evolution may allow a surprising degree of homologous or identical CDR3s associated with individual disease entities, creating hope for novel diagnostics and/or disease burden assessments. Integrating studies of the peripheral blood, lymph nodes, and tumor allows dynamic interrogation of the alterations occurring with age, treatment, and response to emergent and established therapies.

Key words

Adaptome Myelome Immune repertoire Unique CDR3s Diversity index iR-Map T cell receptor B cell receptor Disease-specific linklets 


  1. 1.
    Shitaoka K, Hamana H, Kishi H et al (2018) Identification of tumoricidal TCRs from tumor-infiltrating lymphocytes by single-cell analysis. Cancer Immunol Res 6:378–388PubMedGoogle Scholar
  2. 2.
    Jerne NK, Maaloe O (1949) On standardization of diphtheria toxoid: some theoretical and practical considerations. Bull World Health Organ 2:49–57PubMedPubMedCentralGoogle Scholar
  3. 3.
    Jerne NK (1955) The natural-selection theory of antibody formation. Proc Natl Acad Sci U S A 41:849–857PubMedPubMedCentralGoogle Scholar
  4. 4.
    Rajewsky K, Schirrmacher V, Nase S, Jerne NK (1969) The requirement of more than one antigenic determinant for immunogenicity. J Exp Med 129:1131–1143PubMedPubMedCentralGoogle Scholar
  5. 5.
    Jerne NK (1974) The immune system: a web of V-domains. Harvey Lect 70 Series:93–110PubMedGoogle Scholar
  6. 6.
    Jerne NK (1974) Towards a network theory of the immune system. Ann Immunol (Paris) 125C:373–389Google Scholar
  7. 7.
    Jerne NK (2004) The somatic generation of immune recognition 1971. Eur J Immunol 34:1234–1242PubMedGoogle Scholar
  8. 8.
    Jerne NK (1993) The Nobel lectures in immunology. The Nobel prize for physiology or medicine, 1984. The generative grammar of the immune system. Scand J Immunol 38:1–9PubMedGoogle Scholar
  9. 9.
    Tonegawa S, Steinberg C, Dube S, Bernardini A (1974) Evidence for somatic generation of antibody diversity. Proc Natl Acad Sci U S A 71:4027–4031PubMedPubMedCentralGoogle Scholar
  10. 10.
    Sakano H, Huppi K, Heinrich G, Tonegawa S (1979) Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature 280:288–294PubMedGoogle Scholar
  11. 11.
    Tonegawa S (1983) Somatic generation of antibody diversity. Nature 302:575–581PubMedGoogle Scholar
  12. 12.
    Davis MM, Chien YH, Gascoigne NR, Hedrick SM (1984) A murine T cell receptor gene complex: isolation, structure and rearrangement. Immunol Rev 81:235–258PubMedGoogle Scholar
  13. 13.
    Kavaler J, Davis MM, Chien Y (1984) Localization of a T-cell receptor diversity-region element. Nature 310:421–423PubMedGoogle Scholar
  14. 14.
    Robertson M (1984) Receptor gene rearrangement and ontogeny of T lymphocytes. Nature 311:305–306PubMedGoogle Scholar
  15. 15.
    Royer HD, Acuto O, Fabbi M et al (1984) Genes encoding the Ti beta subunit of the antigen/MHC receptor undergo rearrangement during intrathymic ontogeny prior to surface T3-Ti expression. Cell 39:261–266PubMedGoogle Scholar
  16. 16.
    Siu G, Kronenberg M, Strauss E, Haars R, Mak TW, Hood L (1984) The structure, rearrangement and expression of D beta gene segments of the murine T-cell antigen receptor. Nature 311:344–350PubMedGoogle Scholar
  17. 17.
    Toyonaga B, Mak TW (1987) Genes of the T-cell antigen receptor in normal and malignant T cells. Annu Rev Immunol 5:585–620PubMedGoogle Scholar
  18. 18.
    Minden MD, Mak TW (1986) The structure of the T cell antigen receptor genes in normal and malignant T cells. Blood 68:327–336PubMedGoogle Scholar
  19. 19.
    Griesser H, Feller A, Lennert K et al (1986) The structure of the T cell gamma chain gene in lymphoproliferative disorders and lymphoma cell lines. Blood 68:592–594PubMedGoogle Scholar
  20. 20.
    Hayday AC, Saito H, Gillies SD et al (1985) Structure, organization, and somatic rearrangement of T cell gamma genes. Cell 40:259–269PubMedGoogle Scholar
  21. 21.
    Lefranc MP, Rabbitts TH (1985) Two tandemly organized human genes encoding the T-cell gamma constant-region sequences show multiple rearrangement in different T-cell types. Nature 316:464–466PubMedGoogle Scholar
  22. 22.
    Murre C, Waldmann RA, Morton CC et al (1985) Human gamma-chain genes are rearranged in leukaemic T cells and map to the short arm of chromosome 7. Nature 316:549–552PubMedGoogle Scholar
  23. 23.
    Saada R, Weinberger M, Shahaf G, Mehr R (2007) Models for antigen receptor gene rearrangement: CDR3 length. Immunol Cell Biol 85:323–332PubMedGoogle Scholar
  24. 24.
    Jackson KJ, Kidd MJ, Wang Y, Collins AM (2013) The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor. Front Immunol 4:263PubMedPubMedCentralGoogle Scholar
  25. 25.
    Jackson KJ, Wang Y, Collins AM (2014) Human immunoglobulin classes and subclasses show variability in VDJ gene mutation levels. Immunol Cell Biol 92:729–733PubMedGoogle Scholar
  26. 26.
    Collins AM, Wang Y, Roskin KM, Marquis CP, Jackson KJ (2015) The mouse antibody heavy chain repertoire is germline-focused and highly variable between inbred strains. Philos Trans R Soc Lond Ser B Biol Sci 370. Scholar
  27. 27.
    Collins AM, Jackson KJL (2018) On being the right size: antibody repertoire formation in the mouse and human. Immunogenetics 70:143–158PubMedGoogle Scholar
  28. 28.
    Schuldt NJ, Auger JL, Spanier JA et al (2017) Cutting edge: dual TCRalpha expression poses an autoimmune Hazard by limiting regulatory T cell generation. J Immunol 199:33–38PubMedPubMedCentralGoogle Scholar
  29. 29.
    Peyrat MA, Davodeau F, Houde I et al (1995) Repertoire analysis of human peripheral blood lymphocytes using a human V delta 3 region-specific monoclonal antibody. Characterization of dual T cell receptor (TCR) delta-chain expressors and alpha beta T cells expressing V delta 3J alpha C alpha-encoded TCR chains. J Immunol 155:3060–3067PubMedGoogle Scholar
  30. 30.
    Lotze MT, Zeh HJ, Rubartelli A et al (2007) The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev 220:60–81PubMedGoogle Scholar
  31. 31.
    Tor M, Lotze MT, Holton N (2009) Receptor-mediated signalling in plants: molecular patterns and programmes. J Exp Bot 60:3645–3654PubMedPubMedCentralGoogle Scholar
  32. 32.
    Wu SG, Pan W, Liu H, Byrne-Steele ML, Brown B, Depinet M, Hou X, Han J, Li S (2019) High throughput sequencing of T-cell receptor repertoire using dry blood spots. J Transl Med. 17(1):47PubMedPubMedCentralGoogle Scholar
  33. 33.
    Chorazeczewski JK, Aleshnick M, Majam V et al (2018) TCRbeta combinatorial Immunoreceptor expression by neutrophils correlates with parasite burden and enhanced phagocytosis during a Plasmodium berghei ANKA malaria infection. Infect Immun 86.
  34. 34.
    Fuchs T, Puellmann K, Scharfenstein O et al (2012) The neutrophil recombinatorial TCR-like immune receptor is expressed across the entire human life span but repertoire diversity declines in old age. Biochem Biophys Res Commun 419:309–315PubMedGoogle Scholar
  35. 35.
    Puellmann K, Kaminski WE, Vogel M et al (2006) A variable immunoreceptor in a subpopulation of human neutrophils. Proc Natl Acad Sci U S A 103:14441–14446PubMedPubMedCentralGoogle Scholar
  36. 36.
    Fuchs T, Puellmann K, Wang C, Han J, Beham AW, Neumaier M, Kaminski WE (2019) Trilineage sequencing reveals complex TCRβ transcriptomes in neutrophils and monocytes alongside T cells. Genom Proteom Bioinf. In pressGoogle Scholar
  37. 37.
    Sun X, Saito M, Sato Y et al (2012) Unbiased analysis of TCRalpha/beta chains at the single-cell level in human CD8+ T-cell subsets. PLoS One 7:e40386PubMedPubMedCentralGoogle Scholar
  38. 38.
    Walchli S, Loset GA, Kumari S et al (2011) A practical approach to T-cell receptor cloning and expression. PLoS One 6:e27930PubMedPubMedCentralGoogle Scholar
  39. 39.
    Magurran AE, Henderson PA (2003) Explaining the excess of rare species in natural species abundance distributions. Nature 422:714–716PubMedGoogle Scholar
  40. 40.
    Venturi V, Kedzierska K, Turner SJ et al (2007) Methods for comparing the diversity of samples of the T cell receptor repertoire. J Immunol Methods 321:182–195PubMedGoogle Scholar
  41. 41.
    Puisieux I, Bain C, Merrouche Y et al (1996) Restriction of the T-cell repertoire in tumor-infiltrating lymphocytes from nine patients with renal-cell carcinoma. Relevance of the CDR3 length analysis for the identification of in situ clonal T-cell expansions. Int J Cancer 66:201–208PubMedGoogle Scholar
  42. 42.
    Scholler J, thor Straten P, Birck A et al (1994) Analysis of T cell receptor alpha beta variability in lymphocytes infiltrating melanoma primary tumours and metastatic lesions. Cancer Immunol Immunother 39:239–248PubMedGoogle Scholar
  43. 43.
    Savelieva E, Farace F, Angevin E et al (1994) T-cell receptor repertoire in colorectal adenocarcinoma patients with hepatic metastases and its changes induced by preoperative adjuvant interleukin-2 therapy. J Immunother Emphasis Tumor Immunol 16:66–76PubMedGoogle Scholar
  44. 44.
    Nishimura MI, Kawakami Y, Charmley P et al (1994) T-cell receptor repertoire in tumor-infiltrating lymphocytes. Analysis of melanoma-specific long-term lines. J Immunother Emphasis Tumor Immunol 16:85–94PubMedGoogle Scholar
  45. 45.
    Rojas M, Restrepo-Jimenez P, Monsalve DM et al (2018) Molecular mimicry and autoimmunity. J Autoimmun 95:100–123PubMedGoogle Scholar
  46. 46.
    de Jong A, Jabbari A, Dai Z et al (2018) High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata. JCI Insight 3.
  47. 47.
    Jacobsen LM, Posgai A, Seay HR, Haller MJ, Brusko TM (2017) T cell receptor profiling in type 1 diabetes. Curr Diab Rep 17:118PubMedPubMedCentralGoogle Scholar
  48. 48.
    Yang G, Ou M, Chen H et al (2018) Characteristic analysis of TCR beta-chain CDR3 repertoire for pre- and post-liver transplantation. Oncotarget 9:34506–34519PubMedPubMedCentralGoogle Scholar
  49. 49.
    Sykes M (2018) Immune monitoring of transplant patients in transient mixed chimerism tolerance trials. Hum Immunol 79:334–342PubMedGoogle Scholar
  50. 50.
    Savage TM, Shonts BA, Obradovic A et al (2018) Early expansion of donor-specific Tregs in tolerant kidney transplant recipients. JCI Insight 3.
  51. 51.
    Link-Rachner CS, Eugster A, Rucker-Braun E et al (2019) T cell receptor alpha repertoire of CD8+ T cells following allogeneic stem cell transplantation using next-generation sequencing. Haematologica. Scholar
  52. 52.
    Gkazi AS, Margetts BK, Attenborough T et al (2018) Clinical T cell receptor repertoire deep sequencing and analysis: an application to monitor immune reconstitution following cord blood transplantation. Front Immunol 9:2547PubMedPubMedCentralGoogle Scholar
  53. 53.
    DeWolf S, Grinshpun B, Savage T et al (2018) Quantifying size and diversity of the human T cell alloresponse. JCI Insight 3.
  54. 54.
    Yang Y, Wang C, Yang Q et al (2015) Distinct mechanisms define murine B cell lineage immunoglobulin heavy chain (IgH) repertoires. elife 4:e09083PubMedPubMedCentralGoogle Scholar
  55. 55.
    Rudqvist NP, Pilones KA, Lhuillier C et al (2018) Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells. Cancer Immunol Res 6:139–150PubMedGoogle Scholar
  56. 56.
    Duhen T, Duhen R, Montler R et al (2018) Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun 9:2724PubMedPubMedCentralGoogle Scholar
  57. 57.
    Shi L, Zhang Y, Feng L et al (2017) Multi-omics study revealing the complexity and spatial heterogeneity of tumor-infiltrating lymphocytes in primary liver carcinoma. Oncotarget 8:34844–34857PubMedPubMedCentralGoogle Scholar
  58. 58.
    Sakellariou-Thompson D, Forget MA, Creasy C et al (2017) 4-1BB agonist focuses CD8(+) tumor-infiltrating T-cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer. Clin Cancer Res 23:7263–7275PubMedPubMedCentralGoogle Scholar
  59. 59.
    Rubelt F, Busse CE, Bukhari SAC et al (2017) Adaptive immune receptor repertoire community recommendations for sharing immune-repertoire sequencing data. Nat Immunol 18:1274–1278PubMedPubMedCentralGoogle Scholar
  60. 60.
    Omland SH, Hamrouni A, Gniadecki R (2017) High diversity of the T-cell receptor repertoire of tumor-infiltrating lymphocytes in basal cell carcinoma. Exp Dermatol 26:454–456PubMedGoogle Scholar
  61. 61.
    Miller NJ, Church CD, Dong L et al (2017) Tumor-infiltrating Merkel cell Polyomavirus-specific T cells are diverse and associated with improved patient survival. Cancer Immunol Res 5:137–147PubMedPubMedCentralGoogle Scholar
  62. 62.
    Kato T, Park JH, Kiyotani K, Ikeda Y, Miyoshi Y, Nakamura Y (2017) Integrated analysis of somatic mutations and immune microenvironment of multiple regions in breast cancers. Oncotarget 8:62029–62038PubMedPubMedCentralGoogle Scholar
  63. 63.
    Sims JS, Grinshpun B, Feng Y et al (2016) Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire. Proc Natl Acad Sci U S A 113:E3529–E3537PubMedPubMedCentralGoogle Scholar
  64. 64.
    Saito H, Okita K, Fusaki N, Sabel MS, Chang AE, Ito F (2016) Reprogramming of melanoma tumor-infiltrating lymphocytes to induced pluripotent stem cells. Stem Cells Int 2016:8394960PubMedGoogle Scholar
  65. 65.
    Poschke I, Flossdorf M, Offringa R (2016) Next-generation TCR sequencing - a tool to understand T-cell infiltration in human cancers. J Pathol 240:384–386PubMedGoogle Scholar
  66. 66.
    Poschke I, Faryna M, Bergmann F et al (2016) Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma. Oncoimmunology 5:e1240859PubMedPubMedCentralGoogle Scholar
  67. 67.
    Page DB, Yuan J, Redmond D et al (2016) Deep sequencing of T-cell receptor DNA as a biomarker of clonally expanded TILs in breast Cancer after immunotherapy. Cancer Immunol Res 4:835–844PubMedPubMedCentralGoogle Scholar
  68. 68.
    Chen Z, Zhang C, Pan Y et al (2016) T cell receptor beta-chain repertoire analysis reveals intratumour heterogeneity of tumour-infiltrating lymphocytes in oesophageal squamous cell carcinoma. J Pathol 239:450–458PubMedGoogle Scholar
  69. 69.
    Zhang Q, Jia Q, Deng T, Song B, Li L (2015) Heterogeneous expansion of CD4+ tumor-infiltrating T-lymphocytes in clear cell renal cell carcinomas. Biochem Biophys Res Commun 458:70–76PubMedGoogle Scholar
  70. 70.
    Turcotte S, Gros A, Tran E et al (2014) Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy. Clin Cancer Res 20:331–343PubMedGoogle Scholar
  71. 71.
    Shao H, Ou Y, Wang T et al (2014) Differences in TCR-Vbeta repertoire and effector phenotype between tumor infiltrating lymphocytes and peripheral blood lymphocytes increase with age. PLoS One 9:e102327PubMedPubMedCentralGoogle Scholar
  72. 72.
    Gros A, Robbins PF, Yao X et al (2014) PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Invest 124:2246–2259PubMedPubMedCentralGoogle Scholar
  73. 73.
    Sherwood AM, Emerson RO, Scherer D et al (2013) Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer Immunol Immunother 62:1453–1461PubMedPubMedCentralGoogle Scholar
  74. 74.
    Gerlinger M, Quezada SA, Peggs KS et al (2013) Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J Pathol 231:424–432PubMedPubMedCentralGoogle Scholar
  75. 75.
    Emerson RO, Sherwood AM, Rieder MJ et al (2013) High-throughput sequencing of T-cell receptors reveals a homogeneous repertoire of tumour-infiltrating lymphocytes in ovarian cancer. J Pathol 231:433–440PubMedPubMedCentralGoogle Scholar
  76. 76.
    Junker N, Kvistborg P, Kollgaard T, Straten P, Andersen MH, Svane IM (2012) Tumor associated antigen specific T-cell populations identified in ex vivo expanded TIL cultures. Cell Immunol 273:1–9PubMedGoogle Scholar
  77. 77.
    Hindley JP, Ferreira C, Jones E et al (2011) Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res 71:736–746PubMedGoogle Scholar
  78. 78.
    de Vos van Steenwijk PJ, Heusinkveld M, Ramwadhdoebe TH et al (2010) An unexpectedly large polyclonal repertoire of HPV-specific T cells is poised for action in patients with cervical cancer. Cancer Res 70:2707–2717PubMedGoogle Scholar
  79. 79.
    Simsa P, Teillaud JL, Stott DI, Toth J, Kotlan B (2005) Tumor-infiltrating B cell immunoglobulin variable region gene usage in invasive ductal breast carcinoma. Pathol Oncol Res 11:92–97PubMedGoogle Scholar
  80. 80.
    Pilch H, Hohn H, Neukirch C et al (2002) Antigen-driven T-cell selection in patients with cervical cancer as evidenced by T-cell receptor analysis and recognition of autologous tumor. Clin Diagn Lab Immunol 9:267–278PubMedPubMedCentralGoogle Scholar
  81. 81.
    Zhang XY, Chan WY, Whitney BM et al (2001) T cell receptor Vbeta repertoire expression reflects gastric carcinoma progression. Clin Immunol 101:3–7PubMedGoogle Scholar
  82. 82.
    Deniger DC, Kwong ML, Pasetto A et al (2017) A pilot trial of the combination of Vemurafenib with adoptive cell therapy in patients with metastatic melanoma. Clin Cancer Res 23:351–362PubMedGoogle Scholar
  83. 83.
    Poschke I, Lovgren T, Adamson L et al (2014) A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma. Cancer Immunol Immunother 63:1061–1071PubMedGoogle Scholar
  84. 84.
    DeBruyne LA, Chang AE, Cameron MJ et al (1996) Direct transfer of a foreign MHC gene into human melanoma alters T cell receptor V beta usage by tumor-infiltrating lymphocytes. Cancer Immunol Immunother 43:49–58PubMedGoogle Scholar
  85. 85.
    Weidmann E, Logan TF, Yasumura S, Kirkwood JM, Trucco M, Whiteside TL (1993) Evidence for oligoclonal T-cell response in a metastasis of renal cell carcinoma responding to vaccination with autologous tumor cells and transfer of in vitro-sensitized vaccine-draining lymph node lymphocytes. Cancer Res 53:4745–4749PubMedGoogle Scholar
  86. 86.
    Gros A, Parkhurst MR, Tran E et al (2016) Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med 22:433–438PubMedGoogle Scholar
  87. 87.
    Lu YC, Yao X, Crystal JS et al (2014) Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res 20:3401–3410PubMedPubMedCentralGoogle Scholar
  88. 88.
    Kerkar SP, Muranski P, Kaiser A et al (2010) Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 70:6725–6734PubMedPubMedCentralGoogle Scholar
  89. 89.
    Boni A, Muranski P, Cassard L et al (2008) Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers. Blood 112:4746–4754PubMedPubMedCentralGoogle Scholar
  90. 90.
    Parker LL, Do MT, Westwood JA et al (2000) Expansion and characterization of T cells transduced with a chimeric receptor against ovarian cancer. Hum Gene Ther 11:2377–2387PubMedGoogle Scholar
  91. 91.
    Shilyansky J, Nishimura MI, Yannelli JR et al (1994) T-cell receptor usage by melanoma-specific clonal and highly oligoclonal tumor-infiltrating lymphocyte lines. Proc Natl Acad Sci U S A 91:2829–2833PubMedPubMedCentralGoogle Scholar
  92. 92.
    Giraldo NA, Becht E, Vano Y et al (2017) Tumor-infiltrating and peripheral blood T-cell Immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res 23:4416–4428PubMedGoogle Scholar
  93. 93.
    Cole DJ, Wilson MC, Rivoltini L, Custer M, Nishimura MI (1997) T-cell receptor repertoire in matched MART-1 peptide-stimulated peripheral blood lymphocytes and tumor-infiltrating lymphocytes. Cancer Res 57:5320–5327PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.iRepertoire, Inc.HuntsvilleUSA
  2. 2.Hudson Alpha InstituteHuntsvilleUSA
  3. 3.University of Pittsburgh Medical CenterPittsburghUSA

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