Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation.
Prolonged exposure to interferon-gamma (IFNγ) and the associated increased expression of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage of tryptophan in the cancer cells, which stimulates ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis. Here, we investigated whether such neoepitopes can be useful targets of adoptive T cell therapy. Immunopeptidomic analyses uncovered hundreds of W>F neoepitopes mainly presented by the HLA-A∗24:02 allele. We identified a T cell receptor (TCRTMBIM6W>F.1) possessing high affinity and specificity toward TMBIM6W>F/HLA-A∗24:02, the inducible W>F neoepitope with the broadest expression across cancer cell lines. TCRTMBIM6W>F.1 T cells are activated by tryptophan-depleted cancer cells but not by non-cancer cells. Finally, we provide in vivo proof of concept for clinical application, whereby TCRMART1 T cells promote cancer cell killing by TCRTMBIM6W>F.1 T cells through the generation of W>F neoepitopes. Thus, neoepitopes arising from W>F substitution present shared and highly expressed immunogenic targets with the potential to overcome current limitations in adoptive T cell therapy.
Pubmed ID: 39755122
Research resources used in this publication
- HEK293T (RRID:CVCL_0063) (cell line)
- 888-mel (RRID:CVCL_4632) (cell line)
- MCF-10A (RRID:CVCL_0598) (cell line)
- MDA-MB-435 (RRID:CVCL_0417) (cell line)
- RA (RRID:CVCL_C6JY) (cell line)
- BT-20 (RRID:CVCL_0178) (cell line)
- NCI-H226 (RRID:CVCL_1544) (cell line)
- NCI-H1299 (RRID:CVCL_0060) (cell line)
- WiDr (RRID:CVCL_2760) (cell line)
- Hep-G2 (RRID:CVCL_0027) (cell line)
- DLD-1 (RRID:CVCL_0248) (cell line)
- PC-9 (RRID:CVCL_B260) (cell line)
- MDA-MB-435S (RRID:CVCL_0622) (cell line)
- NCI-H187 (RRID:CVCL_1501) (cell line)
- MDA-MB-231 (RRID:CVCL_0062) (cell line)
- HT-29 (RRID:CVCL_0320) (cell line)
- D10 (RRID:CVCL_H945) (cell line)
- COLO 320 (RRID:CVCL_1989) (cell line)
- HCT 15 (RRID:CVCL_0292) (cell line)
- DU145 (RRID:CVCL_0105) (cell line)
- SW480 (RRID:CVCL_0546) (cell line)
- PC-3 (RRID:CVCL_0035) (cell line)
- hTERT-RPE1 (RRID:CVCL_4388) (cell line)
- MIA PaCa-2 (RRID:CVCL_0428) (cell line)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- CD3 Monoclonal Antibody (OKT3), Functional Grade, eBioscience (RRID:AB_468854)
- F(ab')2-Goat anti-Mouse IgG (H+L) Secondary Antibody, APC, eBioscience (RRID:AB_2573203)
- CD28 Monoclonal Antibody (CD28.6), Functional Grade, eBioscience (RRID:AB_468924)
- Mouse Anti-Human HLA-A24 Monoclonal Antibody, Unconjugated, Clone 17A10 (RRID:AB_592230)
- PE anti-human HLA-A2 (RRID:AB_1877227)
- FITC anti-human CD20 (RRID:AB_314251)
- Mouse Anti-HLA-A,B,C Monoclonal Antibody, FITC Conjugated, Clone G46-2.6 (RRID:AB_395935)
- PE anti-mouse TCR beta chain (RRID:AB_313430)
- APC anti-human beta2-microglobulin (RRID:AB_10643412)
- Alexa Fluor(R) 647 anti-human CD137 (4-1BB) (RRID:AB_2566257)
- HLA-A24-Alexa Fluor®647 (RRID:AB_1953030)
- Brilliant Violet 785(TM) anti-human CD8 (RRID:AB_2566201)
- Mouse Anti-CD8 Monoclonal Antibody, Pacific Blue?? Conjugated, Clone RPA-T8 (RRID:AB_397058)
- PerCP/Cyanine5.5 anti-human CD3 (RRID:AB_893301)
- TCRβ Antibody, anti-mouse, PE, REAfinity™ (RRID:AB_2889766)
- CD137 Antibody, anti-human, APC (RRID:AB_2751905)
- Brilliant Violet 711(TM) anti-human CD4 (RRID:AB_2564392)
- IRDye 680RD Donkey anti-Mouse IgG (RRID:AB_10953628)
- IRDye 800CW Goat anti-Rat IgG (RRID:AB_1850025)
- beta-2 Microglobulin Monoclonal Antibody (34) (RRID:AB_2866634)
- IRDye 800CW Goat anti-Rabbit IgG (RRID:AB_621843)
- IRDye 680RD Donkey anti-Rabbit IgG (RRID:AB_10954442)
- Monoclonal ANTI-FLAG® M2 antibody produced in mouse (RRID:AB_262044)
- IRDye 800CW Goat anti-Mouse IgG1-Specific (RRID:AB_2782997)
- V5 Tag Monoclonal Antibody (SV5-Pk1) (RRID:AB_2556564)
- Rabbit Anti-Stat1, phospho (Tyr701) Monoclonal Antibody, Unconjugated, Clone 58D6 (RRID:AB_561284)
- IDO (D5J4E) Rabbit mAb (RRID:AB_2636818)
- GCN2 Antibody (RRID:AB_2277617)
- Mouse Anti-Human WARS Monoclonal Antibody, Unconjugated, Clone 3A12 (RRID:AB_607288)
- TAP1 Antibody (RRID:AB_2797889)
- Rat Anti-Tubulin, alpha Monoclonal antibody, Unconjugated, Clone yl1/2 (RRID:AB_793541)
Associated grants
- Agency: European Research Council, International
Id: 865805
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This is a list of tools and resources that we have found mentioned in this publication.
CD3 Monoclonal Antibody (OKT3), Functional Grade, eBioscience (antibody)
RRID:AB_468854
This monoclonal targets CD3
View all literature mentionsF(ab')2-Goat anti-Mouse IgG (H+L) Secondary Antibody, APC, eBioscience (antibody)
RRID:AB_2573203
This polyclonal secondary targets IgG (H+L)
View all literature mentionsCD28 Monoclonal Antibody (CD28.6), Functional Grade, eBioscience (antibody)
RRID:AB_468924
This monoclonal targets CD28
View all literature mentionsMouse Anti-Human HLA-A24 Monoclonal Antibody, Unconjugated, Clone 17A10 (antibody)
RRID:AB_592230
This monoclonal targets Human HLA-A24
View all literature mentionsPE anti-human HLA-A2 (antibody)
RRID:AB_1877227
This monoclonal targets HLA-A2
View all literature mentionsFITC anti-human CD20 (antibody)
RRID:AB_314251
This monoclonal targets CD20
View all literature mentionsMouse Anti-HLA-A,B,C Monoclonal Antibody, FITC Conjugated, Clone G46-2.6 (antibody)
RRID:AB_395935
This monoclonal targets HLA-A, B, C
View all literature mentionsPE anti-mouse TCR beta chain (antibody)
RRID:AB_313430
This monoclonal targets TCR beta chain
View all literature mentionsAPC anti-human beta2-microglobulin (antibody)
RRID:AB_10643412
This monoclonal targets beta2-microglobulin
View all literature mentionsAlexa Fluor(R) 647 anti-human CD137 (4-1BB) (antibody)
RRID:AB_2566257
This monoclonal targets CD137
View all literature mentionsHLA-A24-Alexa Fluor®647 (antibody)
RRID:AB_1953030
This monoclonal targets HLA-A24-Alexa Fluor®647
View all literature mentionsBrilliant Violet 785(TM) anti-human CD8 (antibody)
RRID:AB_2566201
This monoclonal targets CD8
View all literature mentionsMouse Anti-CD8 Monoclonal Antibody, Pacific Blue?? Conjugated, Clone RPA-T8 (antibody)
RRID:AB_397058
This monoclonal targets CD8
View all literature mentionsPerCP/Cyanine5.5 anti-human CD3 (antibody)
RRID:AB_893301
This monoclonal targets CD3
View all literature mentionsTCRβ Antibody, anti-mouse, PE, REAfinity™ (antibody)
RRID:AB_2889766
This monoclonal targets TCRβ
View all literature mentionsCD137 Antibody, anti-human, APC (antibody)
RRID:AB_2751905
This monoclonal targets CD137
View all literature mentionsBrilliant Violet 711(TM) anti-human CD4 (antibody)
RRID:AB_2564392
This monoclonal targets CD4
View all literature mentionsIRDye 680RD Donkey anti-Mouse IgG (antibody)
RRID:AB_10953628
This unknown targets IgG
View all literature mentionsIRDye 800CW Goat anti-Rat IgG (antibody)
RRID:AB_1850025
This unknown targets IgG
View all literature mentionsbeta-2 Microglobulin Monoclonal Antibody (34) (antibody)
RRID:AB_2866634
This monoclonal targets beta-2 Microglobulin
View all literature mentionsIRDye 800CW Goat anti-Rabbit IgG (antibody)
RRID:AB_621843
This polyclonal secondary targets IgG
View all literature mentionsIRDye 680RD Donkey anti-Rabbit IgG (antibody)
RRID:AB_10954442
This unknown targets IgG
View all literature mentionsMonoclonal ANTI-FLAG® M2 antibody produced in mouse (antibody)
RRID:AB_262044
This monoclonal targets FLAG
View all literature mentionsIRDye 800CW Goat anti-Mouse IgG1-Specific (antibody)
RRID:AB_2782997
This unknown targets IgG1
View all literature mentionsV5 Tag Monoclonal Antibody (SV5-Pk1) (antibody)
RRID:AB_2556564
This monoclonal targets V5 Tag
View all literature mentionsRabbit Anti-Stat1, phospho (Tyr701) Monoclonal Antibody, Unconjugated, Clone 58D6 (antibody)
RRID:AB_561284
This monoclonal targets Stat1, phospho (Tyr701)
View all literature mentionsIDO (D5J4E) Rabbit mAb (antibody)
RRID:AB_2636818
This monoclonal targets IDO
View all literature mentionsMouse Anti-Human WARS Monoclonal Antibody, Unconjugated, Clone 3A12 (antibody)
RRID:AB_607288
This monoclonal targets Human WARS
View all literature mentionsRat Anti-Tubulin, alpha Monoclonal antibody, Unconjugated, Clone yl1/2 (antibody)
RRID:AB_793541
This monoclonal targets TUBA4A
View all literature mentionsHEK293T (cell line)
RRID:CVCL_0063
Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentions888-mel (cell line)
RRID:CVCL_4632
Cell line 888-mel is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMCF-10A (cell line)
RRID:CVCL_0598
Cell line MCF-10A is a Spontaneously immortalized cell line with a species of origin Homo sapiens
View all literature mentionsMDA-MB-435 (cell line)
RRID:CVCL_0417
Cell line MDA-MB-435 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsBT-20 (cell line)
RRID:CVCL_0178
Cell line BT-20 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsNCI-H226 (cell line)
RRID:CVCL_1544
Cell line NCI-H226 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsNCI-H1299 (cell line)
RRID:CVCL_0060
Cell line NCI-H1299 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsWiDr (cell line)
RRID:CVCL_2760
Cell line WiDr is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHep-G2 (cell line)
RRID:CVCL_0027
Cell line Hep-G2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDLD-1 (cell line)
RRID:CVCL_0248
Cell line DLD-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsPC-9 (cell line)
RRID:CVCL_B260
Cell line PC-9 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMDA-MB-435S (cell line)
RRID:CVCL_0622
Cell line MDA-MB-435S is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsNCI-H187 (cell line)
RRID:CVCL_1501
Cell line NCI-H187 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMDA-MB-231 (cell line)
RRID:CVCL_0062
Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHT-29 (cell line)
RRID:CVCL_0320
Cell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsD10 (cell line)
RRID:CVCL_H945
Cell line D10 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCOLO 320 (cell line)
RRID:CVCL_1989
Cell line COLO 320 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHCT 15 (cell line)
RRID:CVCL_0292
Cell line HCT 15 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDU145 (cell line)
RRID:CVCL_0105
Cell line DU145 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSW480 (cell line)
RRID:CVCL_0546
Cell line SW480 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsPC-3 (cell line)
RRID:CVCL_0035
Cell line PC-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionshTERT-RPE1 (cell line)
RRID:CVCL_4388
Cell line hTERT-RPE1 is a Telomerase immortalized cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMIA PaCa-2 (cell line)
RRID:CVCL_0428
Cell line MIA PaCa-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions
