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Recovery of Immunoglobulin VJ Recombinations from Pancreatic Cancer Exome Files Strongly Correlates with Reduced Survival

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Cancer Microenvironment

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Abstract

We assessed pancreatic cancer, lymphocyte infiltrates with a computational genomics approach. We took advantage of tumor-specimen exome files available from the cancer genome atlas to mine T- and B-cell immune receptor recombinations, using highly efficient, scripted algorithms established in several previous reports. Surprisingly, the results indicated that pancreatic cancer exomes represent one of the highest level yields for immune receptor recombinations, significantly higher than two comparison cancers used in this study, head and neck and bladder cancer. In particular, pancreatic cancer exomes have very large numbers of immunoglobulin light chain recombinations, both with regard to number of samples characterized by recovery of such recombinations and with regard to numbers of recombination reads per sample. These results were consistent with B-cell biomarkers, which emphasized the Th2 nature of the pancreatic lymphocyte infiltrate. The tumor specimen exomes with B-cell immune receptor recombination reads represented a dramatically poor outcome, a result not detected with either the head and neck or bladder cancer datasets. The results presented here support the potential value of immunotherapies designed to engineer a Th2 to Th1 shift in treating certain forms of pancreatic cancer.

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References

  1. Bucheit AD, Davies MA (2014) Emerging insights into resistance to BRAF inhibitors in melanoma. Biochem Pharmacol 87(3):381–389. https://doi.org/10.1016/j.bcp.2013.11.013

    Article  PubMed  CAS  Google Scholar 

  2. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404. https://doi.org/10.1158/2159-8290.CD-12-0095

    Article  PubMed  Google Scholar 

  3. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1. https://doi.org/10.1126/scisignal.2004088

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Ping Z, Siegal GP, Almeida JS, Schnitt SJ, Shen D (2014) Mining genome sequencing data to identify the genomic features linked to breast cancer histopathology. J Pathol Inform 5(1):3. https://doi.org/10.4103/2153-3539.126147

    Article  PubMed  PubMed Central  Google Scholar 

  5. Inman BA, Longo TA, Ramalingam S, Harrison MR (2016) Atezolizumab: a PD-L1 blocking antibody for bladder cancer. Clin Cancer Res 23(8):1886–1890. https://doi.org/10.1158/1078-0432.CCR-16-1417

    Article  PubMed  CAS  Google Scholar 

  6. Gupta S, Gill D, Poole A, Agarwal N (2017) Systemic immunotherapy for urothelial cancer: current trends and future directions. Cancers 9(2). https://doi.org/10.3390/cancers9020015

  7. Margolin K (2016) The promise of molecularly targeted and immunotherapy for advanced melanoma. Curr Treat Options in Oncol 17(9):48. https://doi.org/10.1007/s11864-016-0421-5

    Article  Google Scholar 

  8. Yun S, Vincelette ND, Green MR, Wahner Hendrickson AE, Abraham I (2016) Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials. Cancer Med 5(7):1481–1491. https://doi.org/10.1002/cam4.732

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Poschke I, Faryna M, Bergmann F, Flossdorf M, Lauenstein C, Hermes J, Hinz U, Hank T, Ehrenberg R, Volkmar M, Loewer M, Glimm H, Hackert T, Sprick MR, Höfer T, Trumpp A, Halama N, Hassel JC, Strobel O, Büchler M, Sahin U, Offringa R (2016) Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma. Oncoimmunology 5(12):e1240859. https://doi.org/10.1080/2162402X.2016.1240859

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Gill TR, Samy MD, Butler SN, Mauro JA, Sexton WJ, Blanck G (2016) Detection of productively rearranged TcR-alpha V-J sequences in TCGA exome files: implications for tumor Immunoscoring and recovery of antitumor T-cells. Cancer Inform 15:23–28. https://doi.org/10.4137/CIN.S35784

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Tong WL, Tu YN, Samy MD, Sexton WJ, Blanck G (2017) Identification of immunoglobulin V(D)J recombinations in solid tumor specimen exome files: evidence for high level B-cell infiltrates in breast cancer. Hum Vaccin Immunother 13(3):1–6. https://doi.org/10.1080/21645515.2016.1246095

    Article  Google Scholar 

  12. Levy E, Marty R, Garate Calderon V, Woo B, Dow M, Armisen R et al (2016) Immune DNA signature of T-cell infiltration in breast tumor exomes. Sci Rep 6(1):30064. https://doi.org/10.1038/srep30064

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Brown SD, Raeburn LA, Holt RA (2015) Profiling tissue-resident T cell repertoires by RNA sequencing. Genome Med 7(1):125. https://doi.org/10.1186/s13073-015-0248-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Butler SN, Blanck G (2016) Immunoscoring by correlating MHC class II and TCR expression: high level immune functions represented by the KIRP dataset of TCGA. Cell Tissue Res 363(2):491–496. https://doi.org/10.1007/s00441-015-2261-1

    Article  PubMed  CAS  Google Scholar 

  15. Redmond D, Poran A, Elemento O (2016) Single-cell TCRseq: paired recovery of entire T-cell alpha and beta chain transcripts in T-cell receptors from single-cell RNAseq. Genome Med 8(1):80. https://doi.org/10.1186/s13073-016-0335-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Blachly JS, Ruppert AS, Zhao W, Long S, Flynn J, Flinn I, Jones J, Maddocks K, Andritsos L, Ghia EM, Rassenti LZ, Kipps TJ, de la Chapelle A, Byrd JC (2015) Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 112(14):4322–4327. https://doi.org/10.1073/pnas.1503587112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Li B, Li T, Wang B, Dou R, Zhang J, Liu JS, Liu XS (2017) Ultrasensitive detection of TCR hypervariable-region sequences in solid-tissue RNA-seq data. Nat Genet 49(4):482–483. https://doi.org/10.1038/ng.3820

    Article  PubMed  CAS  Google Scholar 

  18. Samy MD, Tong WL, Yavorski JM, Sexton WJ, Blanck G (2017) T cell receptor gene recombinations in human tumor specimen exome files: detection of T cell receptor-beta VDJ recombinations associates with a favorable oncologic outcome for bladder cancer. Cancer Immunol Immunother 66(3):403–410. https://doi.org/10.1007/s00262-016-1943-1

    Article  PubMed  CAS  Google Scholar 

  19. Tu YN, Tong WL, Samy MD, Yavorski JM, Kim M, Blanck G (2017) Assessing microenvironment immunogenicity using tumor specimen exomes: co-detection of TcR-alpha/beta V(D)J recombinations correlates with PD-1 expression. Int J Cancer 140(11):2568–2576. https://doi.org/10.1002/ijc.30675

    Article  PubMed  CAS  Google Scholar 

  20. Giudicelli V, Duroux P, Ginestoux C, Folch G, Jabado-Michaloud J, Chaume D, Lefranc MP (2006) IMGT/LIGM-DB, the IMGT comprehensive database of immunoglobulin and T cell receptor nucleotide sequences. Nucleic Acids Res 34(Database issue):D781–D784. https://doi.org/10.1093/nar/gkj088

    Article  PubMed  CAS  Google Scholar 

  21. Cosmi L, Annunziato F, Galli MIG, Maggi RME, Nagata K, Romagnani S (2000) CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur J Immunol 30(10):2972–2979. https://doi.org/10.1002/1521-4141(200010)30:10<2972::AID-IMMU2972>3.0.CO;2-#

  22. Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D, Gavert N, Zwang Y, Cooper ZA, Shee K, Thaiss CA, Reuben A, Livny J, Avraham R, Frederick DT, Ligorio M, Chatman K, Johnston SE, Mosher CM, Brandis A, Fuks G, Gurbatri C, Gopalakrishnan V, Kim M, Hurd MW, Katz M, Fleming J, Maitra A, Smith DA, Skalak M, Bu J, Michaud M, Trauger SA, Barshack I, Golan T, Sandbank J, Flaherty KT, Mandinova A, Garrett WS, Thayer SP, Ferrone CR, Huttenhower C, Bhatia SN, Gevers D, Wargo JA, Golub TR, Straussman R (2017) Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357(6356):1156–1160. https://doi.org/10.1126/science.aah5043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Tempero MA, Arnoletti JP, Behrman SW, Ben-Josef E, Benson AB 3rd, Casper ES et al (2012) Pancreatic adenocarcinoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw 10(6):703–713. https://doi.org/10.6004/jnccn.2012.0073

    Article  CAS  Google Scholar 

  24. Masso-Valles D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, Whitfield JR, Beaulieu ME, Evan GI, Elias L, Arribas J, Soucek L (2015) Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res 75(8):1675–1681. https://doi.org/10.1158/0008-5472.CAN-14-2852

    Article  PubMed  CAS  Google Scholar 

  25. Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, Gorjestani S, Liudahl SM, Truitt M, Olson P, Kim G, Hanahan D, Tempero MA, Sheppard B, Irving B, Chang BY, Varner JA, Coussens LM (2016) Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov 6(3):270–285. https://doi.org/10.1158/2159-8290.CD-15-0827

    Article  PubMed  CAS  Google Scholar 

  26. Szekeres K, Koul R, Mauro J, Lloyd M, Johnson J, Blanck G (2014) An Oct-1-based, feed-forward mechanism of apoptosis inhibited by co-culture with Raji B-cells: towards a model of the cancer cell/B-cell microenvironment. Exp Mol Pathol 97(3):585–589. https://doi.org/10.1016/j.yexmp.2014.09.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kaneda MM, Cappello P, Nguyen AV, Ralainirina N, Hardamon CR, Foubert P, Schmid MC, Sun P, Mose E, Bouvet M, Lowy AM, Valasek MA, Sasik R, Novelli F, Hirsch E, Varner JA (2016) Macrophage PI3Kgamma drives pancreatic ductal adenocarcinoma progression. Cancer Discov 6(8):870–885. https://doi.org/10.1158/2159-8290.CD-15-1346

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

Authors would like to acknowledge the support of the USF research computing facility and the taxpayers of the State of Florida. This work is dedicated to Keith.

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Authors and Affiliations

  1. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Bd. MDC7, Tampa, FL, 33612, USA

    Jacob C. Kinskey, Yaping N. Tu, Wei Lue Tong, John M. Yavorski & George Blanck

  2. Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    George Blanck

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  1. Jacob C. Kinskey
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  2. Yaping N. Tu
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  3. Wei Lue Tong
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  4. John M. Yavorski
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Correspondence to George Blanck.

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Key Points

• A very high level of lymphocyte infiltrate in pancreatic cancer, as evidenced by an immunogenomics approach.

• A clear Th2 character to the lymphocyte infiltrate.

• A significantly worse survival rate for pancreatic cancer patients with demonstrable immunoglobulin light chain recombinations detected in the microenvironment.

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Kinskey, J.C., Tu, Y.N., Tong, W.L. et al. Recovery of Immunoglobulin VJ Recombinations from Pancreatic Cancer Exome Files Strongly Correlates with Reduced Survival. Cancer Microenvironment 11, 51–59 (2018). https://doi.org/10.1007/s12307-018-0205-5

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  • DOI: https://doi.org/10.1007/s12307-018-0205-5

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