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EACR25 symposium Noel F.C.C. de Miranda Immunogenetics Lab
Fingerprinting immune responses and improving immunotherapies with TCR sequencing
1 Insert > Header & footer 4-Jul-18
Antigen presentation and T cell recognition
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immunotherapies with TCR sequencing EACR25 symposium Noel F.C.C. de - - PowerPoint PPT Presentation
immunotherapies with TCR sequencing EACR25 symposium Noel F.C.C. de - - PowerPoint PPT Presentation
Fingerprinting immune responses and improving immunotherapies with TCR sequencing EACR25 symposium Noel F.C.C. de Miranda Immunogenetics Lab HLA II - neoantigen TCR Deng L et al . Nat Immunol 2017 1 Insert > Header & footer
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Antigen presentation and T cell recognition
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HLA-A*02:01 HLA-A*11:01
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Antigen presentation and T cell recognition
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Reinherz, E.L, et al. Science. 1999 Hennecke & Wiley Cell 2001
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Mutation burden and response to checkpoint blockade
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Yarchoan M, et al. NEJM 2017
DNA repair defects UV damage Smoking damage Higher probability of Neo-antigen presentation And T cell recogition
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TCR diversity – V(D)J recombination
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Turner et al. NatRev Immunol 2006
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CDR regions – T cell molecular barcodes
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Hennecke & Wiley Cell 2001
>300 bp (RNA) 400 bp read-length
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Els Verdegaal Sjoerd van der Burg
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Adoptive T-cell transfer in melanoma
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Stage IV melanoma patient AB
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MLTC T cell reactivity
Exome sequencing
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Stage IV melanoma patient AB
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TIL 04.01 MLTC 04.01 TIL 08.01 TIL 12.07 TIL 12.09
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Stage IV melanoma patient AB
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TIL 04.01 MLTC 04.01 TIL 08.01 TIL 12.07 TIL 12.09
04.01 tumor tissue
SEPT2 R300C
08.01 tumor tissue 12.09 tumor tissue
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Stage IV melanoma patient AB
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MLTC 04.01 TIL 12.07
Gene expression
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Stage IV melanoma patient AB
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Was tumor immunoediting and response to therapy driven by the ACT treatment?
Ion AmpliSeq Immune Repertoire Assay
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Stage IV melanoma patient AB
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TIL 04.01 MLTC 04.01 TIL 08.01 TIL 12.07 TIL 12.09
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TIL 04.01
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Clones: 11118, Shannon diversity: 10,7217, Clone evenness: 0,7977
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MLTC 04.01
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Clones: 2716; Shannon diversity: 8,4940; Clone evenness: 0,7446
SLIDE 18
Matchmaking – CDR 3 sequences
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TIL 04.01 386 clones in common with MLTC 04.01 (3.5% of clones, 23% of reads)
Variable Joining CDR3 AA CDR3 NT Diversity Frequency TRBV9 TRBJ1-1 ASHGQGVGEAF GCCAGCCACGGACAGGGGGTTGGTGAAGCTTTC TRBD1 0.050681 TRBV29-1 TRBJ2-1 SVAGGRAGEQF AGCGTTGCTGGCGGGAGGGCCGGTGAGCAGTTC TRBD2 0.02175 TRBV5-6 TRBJ2-3 ASSTQSGVTQY GCCAGCAGCACCCAGAGCGGGGTTACGCAGTAT TRBD2 0.013705 TRBV6-6 TRBJ2-3 ASTQARGTDTQY GCCAGCACTCAGGCCCGTGGCACAGATACGCAGTAT 0.011479 TRBV12-4 TRBJ2-1 ASSLAGSIDEQF GCCAGCAGTTTAGCGGGTTCCATTGATGAGCAGTTC TRBD2 0.011431 TRBV3-1 TRBJ2-1 ASSQGLDSYNEQF GCCAGCAGCCAAGGACTTGACTCCTACAATGAGCAGTTC TRBD2 0.010884 TRBV7-6 TRBJ2-2 ASSPPGPGTGELF GCCAGCAGCCCGCCGGGGCCTGGCACCGGGGAGCTGTTT TRBD1 0.010861 TRBV12-3 TRBJ2-5 ASSLGRAGWETQY GCCAGCAGTTTAGGTCGAGCGGGGTGGGAGACCCAGTAC TRBD2 0.008158 TRBV7-2 TRBJ1-2 ASSLADLANYGYT GCCAGCAGCTTAGCGGATCTAGCTAACTATGGCTACACC TRBD2 0.007764 TRBV3-1 TRBJ2-4 ASSPRTTPTWNIQY GCCAGCAGCCCAAGGACTACGCCGACCTGGAACATTCAGTAC TRBD2 0.006712 TRBV5-4 TRBJ1-1 ASSTDRNTEAF GCCAGCAGCACCGACAGGAACACTGAAGCTTTC TRBD1 0.006612 TRBV9 TRBJ2-7 ASSMTGLGNEQY GCCAGCAGCATGACAGGTCTGGGCAACGAGCAGTAC TRBD1 0.006181 TRBV2 TRBJ2-1 ASSGRRHEQF GCCAGCAGTGGTAGAAGGCATGAGCAGTTC 0.006084 TRBV7-7 TRBJ2-7 ASSPGTNEFYEQY GCCAGCAGCCCCGGGACTAATGAATTTTACGAGCAGTAC TRBD2 0.005142 TRBV4-1 TRBJ2-7 ASSQEIRRQSSYEQY GCCAGCAGCCAAGAAATTAGGAGACAGAGCTCCTACGAGCAGTAC TRBD1 0.004753 TRBV7-9 TRBJ2-3 ASRGLAVSNTQY GCCAGCAGGGGACTGGCGGTTTCAAATACGCAGTAT TRBD1 0.00448 TRBV29-1 TRBJ2-7 SVAPRGGSYEQY AGCGTCGCACCGCGTGGGGGCTCCTACGAGCAGTAC TRBD1 0.004417 TRBV6-4 TRBJ2-2 ASSDSRGRDTGELF GCCAGCAGTGACTCGAGAGGGAGAGACACCGGGGAGCTGTTT TRBD2 0.00438 TRBV6-1 TRBJ2-1 ASREYGEQF GCCAGCAGGGAATATGGTGAGCAGTTC 0.004191 TRBV12-4 TRBJ1-2 ASSLPGGPGYT GCCAGCAGTTTACCCGGAGGACCTGGCTACACC TRBD2 0.004183 TRBV20-1 TRBJ1-1 SASSSDRPNTEAF AGTGCTAGTAGTAGCGACAGGCCGAACACTGAAGCTTTC TRBD1 0.003886 TRBV13 TRBJ2-7 ASSLAPGLAAEQY GCCAGCAGCTTAGCCCCGGGACTAGCAGCCGAGCAGTAC TRBD2 0.003881
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TIL 04.01 vs MLTC 04.01
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TIL 04.01 MLTC 04.01 386 clones in common with TIL 04.01 (14% of clones, 37% of reads) 386 clones in common with MLTC 04.01 (3.5% of clones, 23% of reads)
SLIDE 20
TIL12.07 and TIL12.09
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TIL 12.07 TIL 12.09
Clones: 591, Shannon diversity: 2,3160, Clone evenness: 0,3078 Clones: 3898, Shannon diversity: 6,9033, Clone evenness: 0,5787
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TIL12.07 and TIL12.09
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TIL 12.07 TIL 12.09 95 clones in common with MLTC 04.01 (16% of clones, 86% of reads!!!)
0.07% 0.4%
226 clones in common with MLTC 04.01 (5.8% of clones, 45% of reads!!!)
0.3% 0.06% 0.2% 0.04% 0.1%
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Adapting immunotherapeutic interventions based
- n TCR profiling
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TIL 12.07 12.07 TIL 12.07 TIL 12.09
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More or less diversity?
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TIL 12.07 TIL 04.01
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T cell repertoire before/during checkpoint blockade
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TIL 12.07
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Acknowledgments
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