Abstract
Purpose
Immune characterizations of cancers, including breast cancer, have led to information useful for prognoses and are considered to be important in the future of refining the use of immunotherapies, including immune checkpoint inhibitor therapies. In this study, we sought to extend these characterizations with genomics approaches, particularly with cost-effective employment of exome files.
Methods
By recovery of immune receptor recombination reads from the cancer genome atlas (TCGA) breast cancer dataset, we observed associations of these recombinations with T-cell and B-cell biomarkers and with distinct survival rates.
Results
Recovery of TRD or IGH recombination reads was associated with an improved disease-free survival (p = 0.047 and 0.045, respectively). Determination of the HLA types using the exome files allowed matching of T-cell receptor V- and J-gene segment usage with specific HLA alleles, in turn allowing a refinement of the association of immune receptor recombination read recoveries with survival. For example, the TRBV7, HLA-C*07:01 combination represented a significantly worse, disease-free outcome (p = 0.014) compared to all other breast cancer samples. By direct comparisons of distinct TRB gene segment usage, HLA allele combinations revealed breast cancer subgroups, within the entire TCGA breast cancer dataset with even more dramatic survival distinctions.
Conclusions
In sum, the use of exome files for recovery of adaptive immune receptor recombination reads, and the simultaneous determination of HLA types, has the potential of advancing the use of immunogenomics for immune characterization of breast tumor samples.
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Abbreviations
- BCR:
-
B-cell receptor
- BRCA:
-
Breast cancer
- DFS:
-
Disease-free survival
- ER:
-
Estrogen receptor
- GDC:
-
Genomic data commons
- HLA:
-
human leukocyte antigen
- IGH:
-
Immunoglobulin heavy gene
- IGK:
-
Immunoglobulin kappa gene
- IGL:
-
immunoglobulin lambda gene
- IMGT:
-
ImmunoGeneTics organization
- KM:
-
Kaplan–Meier
- OS:
-
Overall survival
- PR:
-
Progesterone receptor
- TCGA:
-
The cancer genome atlas
- TIL:
-
Tumor-infiltrating lymphocyte
- TCR:
-
T-cell receptor
- TNBC:
-
Triple-negative breast cancer (negative for ER, PR, and HER2)
- TRA:
-
T-cell receptor alpha gene
- TRB:
-
T-cell receptor beta gene
- TRG:
-
T-cell receptor gamma gene
- TRD:
-
T-cell receptor delta gene
- WXS:
-
Whole exome file
References
Whiteside TL, Ferrone S (2012) For breast cancer prognosis, immunoglobulin kappa chain surfaces to the top. Clinical Cancer Res 18:2417–2419
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 8:62029–62038
Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, Boehm D, Gebhard S, Petry I, Lebrecht A, Cadenas C, Marchan R, Stewart JD, Solbach C, Holmberg L, Edlund K, Kultima HG, Rody A, Berglund A, Lambe M, Isaksson A, Botling J, Karn T, Muller V, Gerhold-Ay A, Cotarelo C, Sebastian M, Kronenwett R, Bojar H, Lehr HA, Sahin U, Koelbl H, Gehrmann M, Micke P, Rahnenfuhrer J, Hengstler JG (2012) A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors, Clinical Cancer Res 18: 2695–2703
Fournie JJ, Sicard H, Poupot M, Bezombes C, Blanc A, Romagne F, Ysebaert L, Laurent G (2013) What lessons can be learned from gammadelta T cell-based cancer immunotherapy trials? Cell Mol Immunol 10:35–41
Tu YN, Tong WL, Yavorski JM, Blanck G (2018) Immunogenomics: a negative prostate cancer outcome associated with TcR-gamma/delta recombinations. Cancer Microenviron 11(1):41–49
Callahan BM, Yavorski JM, Tu YN, Tong WL, Kinskey JC, Clark KR, Fawcett TJ, Blanck G (2018) T-cell receptor-beta V and J usage, in combination with particular HLA class I and class II alleles, correlates with cancer survival patterns. Cancer Immunol Immunother 67(6):885–892
Callahan BM, Tong WL, Blanck G (2018) T cell receptor-beta J usage, in combination with particular HLA class II alleles, correlates with better cancer survival rates. Immunol Res 66:219–223
Malaspinas AS, Tange O, Moreno-Mayar JV, Rasmussen M, DeGiorgio M, Wang Y, Valdiosera CE, Politis G, Willerslev E, Nielsen R. (2014) bammds: a tool for assessing the ancestry of low-depth whole-genome data using multidimensional scaling (MDS), Bioinformatics, 30 2962–2964
Tange O (2011) Gnu parallel-the command-line power tool. USENIX Mag 36:42–47
Govindan S, Choi J, Urgaonkar B, Sivasubramaniam A, Baldini A (2009) Statistical profiling-based techniques for effective power provisioning in data centers. Proceedings of the 4th ACM European conference on Computer systems, ACM, pp. 317–330
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 Inf 5:3
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:pl1
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 2:401–404
Xie C, Yeo ZX, Wong M, Piper J, Long T, Kirkness EF, Biggs WH, Bloom K, Spellman S, Vierra-Green C, Brady C, Scheuermann RH, Telenti A, Howard S, Brewerton S, Turpaz Y, Venter JC (2017) Fast and accurate HLA typing from short-read next-generation sequence data with xHLA. Proc Natl Acad Sci USA 114:8059–8064
Callahan BM, Patel JS, Fawcett TJ, Blanck G (2018) Cytoskeleton and ECM tumor mutant peptides: increased protease sensitivities and potential consequences for the HLA class I mutant epitope reservoir. Int J Cancer 142:988–998
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
Mai AT, Tong WL, Tu YN, Blanck G (2018) T-cell receptor-alpha recombinations in renal cell carcinoma exome files correlate with an intermediate level of T-cell exhaustion biomarkers. Int immunol 30:35–40
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. Human Vaccin Immunother 13:501–506
Christiansson L, Soderlund S, Mangsbo S, Hjorth-Hansen H, Hoglund M, Markevarn B, Richter J, Stenke L, Mustjoki S, Loskog A, Olsson-Stromberg U (2015) The tyrosine kinase inhibitors imatinib and dasatinib reduce myeloid suppressor cells and release effector lymphocyte responses. Mol Cancer Ther 14:1181–1191
Steimle V, Otten LA, Zufferey M, Mach B (1993) Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome), Cell 75:135–146
Chae YK, Arya A, Iams W, Cruz MR, Chandra S, Choi J, Giles F (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer 6:39
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 357:1156–1160
Kinskey JC, Tu YN, Tong WL, Yavorski JM, Blanck G (2018) Recovery of immunoglobulin VJ recombinations from pancreatic cancer exome files strongly correlates with reduced survival, Cancer Microenviron 11(1):51–59
Li B, Li T, Pignon JC, Wang B, Wang J, Shukla SA, Dou R, Chen Q, Hodi FS, Choueiri TK, Wu C, Hacohen N, Signoretti S, Liu JS, Liu XS (2016) Landscape of tumor-infiltrating T cell repertoire of human cancers. Nat Genet 48:725–732
Levy E, Marty R, Garate Calderon V, Woo B, Dow M, Armisen R, Carter H, Harismendy O (2016) Immune DNA signature of T-cell infiltration in breast tumor exomes. Sci Rep 6:30064
Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG (2016) Genomic analysis of immune cell infiltrates across 11 tumor types, J Natl Cancer Inst, https://doi.org/10.1093/jnci/djw144
Brown SD, Raeburn LA, Holt RA (2015) Profiling tissue-resident T cell repertoires by RNA sequencing. Genome Med 7:125
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 66:403–410
Tu YN, Tong WL, Fawcett TJ, Blanck G (2017) Lung tumor exome files with T-cell receptor recombinations: a mouse model of T-cell infiltrates reflecting mutation burdens. Lab Invest 97:1516–1520
In TSH, Trotman-Grant A, Fahl S, Chen ELY, Zarin P, Moore AJ, Wiest DL, Zuniga-Pflucker JC, Anderson MK (2017) HEB is required for the specification of fetal IL-17-producing gammadelta T cells. Nat Commun 8:2004
Arias-Pulido H, Cimino-Mathews A, Chaher N, Qualls C, Joste N, Colpaert C, Marotti JD, Foisey M, Prossnitz ER, Emens LA, Fiering S (2018) The combined presence of CD20 + B cells and PD-L1 + tumor-infiltrating lymphocytes in inflammatory breast cancer is prognostic of improved patient outcome, Breast Cancer Res Treat, 171(2):273–282
Lang Kuhs KA, Lin SW, Hua X, Schiffman M, Burk RD, Rodriguez AC, Herrero R, Abnet CC, Freedman ND, Pinto LA, Hamm D, Robins H, Hildesheim A, Shi J, Safaeian M (2018) T cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: an exploratory proof-of-principle study. PLoS ONE 13:e0178167
Zeng G, Huang Y, Huang Y, Lyu Z, Lesniak D, Randhawa P (2016) Antigen-specificity of T cell infiltrates in biopsies with T cell-mediated rejection and BK polyomavirus viremia: analysis by next generation sequencing. Am J Transplant 16:3131–3138
Di Sante G, Tolusso B, Fedele AL, Gremese E, Alivernini S, Nicolo C, Ria F, Ferraccioli G (2015) Collagen specific T-cell repertoire and HLA-DR alleles: biomarkers of active refractory rheumatoid arthritis, EBioMedicine, 2:2037–2045
Klarenbeek PL, Doorenspleet ME, Esveldt RE, van Schaik BD, Lardy N, van Kampen AH, Tak PP, Plenge RM, Baas F, de Bakker PI, de Vries N (2015) Somatic variation of T-cell receptor genes strongly associate with HLA class restriction. PLoS ONE 10:e0140815
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25:1544–1550
Xu T, He BS, Liu XX, Hu XX, Lin K, Pan YQ, Sun HL, Peng HX, Chen XX, Wang SK (2017) The predictive and prognostic role of stromal tumor-infiltrating lymphocytes in HER2−positive breast cancer with trastuzumab-based treatment: a meta-analysis and systematic review. J Cancer 8:3838–3848
Loi S (2013) Tumor-infiltrating lymphocytes, breast cancer subtypes and therapeutic efficacy, Oncoimmunology, 2:e24720
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol 31:860–867
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Authors gratefully acknowledge the support of USF research computing and the taxpayers of the State of Florida. This study is dedicated to Frances.
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Tong, W.L., Callahan, B.M., Tu, Y.N. et al. Immune receptor recombinations from breast cancer exome files, independently and in combination with specific HLA alleles, correlate with better survival rates. Breast Cancer Res Treat 173, 167–177 (2019). https://doi.org/10.1007/s10549-018-4961-1
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DOI: https://doi.org/10.1007/s10549-018-4961-1