Publications
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Douvlataniotis, Dimitrios Karolos; Titov, Aleksei; Zeun, Julia; Bilici, Merve; Palashati, Heyilimu & Loh, Waywen
[Show all 23 contributors for this article]
(2026).
TCR T cells targeting IgA- and IgG-expressing multiple myeloma∗.
Blood.
ISSN 0006-4971.
doi:
10.1182/blood.2025031897.
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T cell-based therapies have shown remarkable efficacy in multiple myeloma (MM), yet the disease remains largely incurable. Here, we investigated the constant domains of the immunoglobulin heavy chain (IgH) as novel targets for therapeutic T cell receptors (TCRs), after confirming high and homogeneous IGH expression in >95% of MM patients. MM cells secrete excessive monoclonal immunoglobulins (M-proteins) that drive complications but are inaccessible to CAR T-cell or antibody targeting. Peptides from IgA and IgG constant regions were eluted from HLA-A*02:01, and reactive TCRs were isolated from healthy donors using allo-HLA-A*02:01 presentation to circumvent self-tolerance. T cells engineered with two TCRs specific for IgA or IgG passed a stringent multi-tier safety screen and selectively eliminated MM cells from 20 HLA-A*02:01+ patients secreting the relevant IgH in vitro. In vivo, IgA-TCR T cells eradicated IgA+HLA-A*02:01+ MM cells in xenograft models and reduced circulating IgA in humanized mice. These findings establish immunoglobulin constant domains as viable TCR targets in MM, potentially making ~40% of patients of European descent eligible for TCR T cell therapy, and extension to additional HLA alleles could further broaden eligibility. The approach may also be applicable to lymphoma and antibody-mediated autoimmune diseases.
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Eggebø, Maria Stadheim; Heinzelbecker, Julia; Palashati, Heyilimu; Chandler, Nicholas John; Tran, Trung & Li, Yingqian
[Show all 15 contributors for this article]
(2025).
TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors.
Nature Immunology.
ISSN 1529-2908.
26,
p. 1726–1736.
doi:
10.1038/s41590-025-02252-1.
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HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy.
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Weller, Chen; Bartok, Osnat; McGinnis, Christopher S.; Palashati, Heyilimu; Chang, Tian-Gen & Malko, Dmitry
[Show all 47 contributors for this article]
(2025).
Translation dysregulation in cancer as a source for targetable antigens.
Cancer Cell.
ISSN 1535-6108.
43(5),
p. 823–840.
doi:
10.1016/j.ccell.2025.03.003.
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Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells. Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies. To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides. Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients. Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy.
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Champagne, Julien; Nielsen, Morten Milek; Feng, Xiaodong; Navarro, Jasmine Montenegro; Pataskar, Abhijeet & Voogd, Rhianne
[Show all 24 contributors for this article]
(2025).
Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation.
Immunity.
ISSN 1074-7613.
58(1),
p. 247–262.e9.
doi:
10.1016/j.immuni.2024.12.004.
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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.
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Giannakopoulou, Eirini Chrysovalantou; Lehander, Madeleine; Culleton, Stina Virding; Yang, Weiwen; Li, Yingqian & Kärpänen, Terhi Hannele
[Show all 29 contributors for this article]
(2023).
A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.
Nature Cancer.
4(10).
doi:
10.1038/s43018-023-00642-8.
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Abstract Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCR FLT3D/Y ). TCR FLT3D/Y -redirected T cells selectively eliminated primary human AML cells harboring the FLT3 D835Y mutation in vitro and in vivo. TCR FLT3D/Y cells rejected both CD34 + and CD34 − AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34 + AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.
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Meyer, Saskia; Blaas, Isaac; Bollineni, Ravi Chand; Delic-Sarac, Marina; Tran, Trung & Knetter, Cathrine
[Show all 20 contributors for this article]
(2023).
Prevalent and immunodominant CD8 T cell epitopes are conserved in SARS-CoV-2 variants.
Cell reports.
42(1).
doi:
10.1016/j.celrep.2023.111995.
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The emergence of SARS-CoV-2 variants of concern (VOC) is driven by mutations that mediate escape from neutralizing antibodies. There is also evidence that mutations can cause loss of T cell epitopes. However, studies on viral escape from T cell immunity have been hampered by uncertain estimates of epitope prevalence. Here, we map and quantify CD8 T cell responses to SARS-CoV-2-specific minimal epitopes in blood drawn from April to June 2020 from 83 COVID-19 convalescents. Among 37 HLA ligands eluted from five prevalent alleles and an additional 86 predicted binders, we identify 29 epitopes with an immunoprevalence ranging from 3% to 100% among individuals expressing the relevant HLA allele. Mutations in VOC are reported in 10.3% of the epitopes, while 20.6% of the non-immunogenic peptides are mutated in VOC. The nine most prevalent epitopes are conserved in VOC. Thus, comprehensive mapping of epitope prevalence does not provide evidence that mutations in VOC are driven by escape of T cell immunity.
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Ali, Muhammad; Giannakopoulou, Eirini Chrysovalantou; Li, Yingqian; Lehander, Madeleine; Culleton, Stina Virding & Yang, Weiwen
[Show all 33 contributors for this article]
(2021).
T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
Nature Biotechnology.
ISSN 1087-0156.
doi:
10.1038/s41587-021-01089-x.
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Abstract Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
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Oei, Vincent Yi Sheng; Siernicka, Marta; Graczyk-Jarzynka, Agnieszka; Hoel, Hanna Julie; Yang, Weiwen & Orellana, Daniel Alfredo Palacios
[Show all 17 contributors for this article]
(2018).
Intrinsic functional potential of NK-Cell subsets constrains retargeting driven by chimeric antigen receptors.
Cancer immunology research.
ISSN 2326-6066.
6(4),
p. 467–480.
doi:
10.1158/2326-6066.CIR-17-0207.
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Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19+ targets, and maintained their intrinsic degranulation response toward CD19− K562 cells. The response of redirected NK-cell subsets against CD19+ targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA–specific KIR(s), displayed superior ability to kill CD19+, HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells.
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Tadesse, Fitsum G.; Mensali, Nadia; Fallang, Lars-Egil; Walseng, Even; Yang, Weiwen & Olweus, Johanna
[Show all 7 contributors for this article]
(2015).
Unpredicted phenotypes of two mutants of the TcR DMF5.
Journal of Immunological Methods (JIM).
ISSN 0022-1759.
425,
p. 37–44.
doi:
10.1016/j.jim.2015.06.006.
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When a T-cell Receptor (TcR) interacts with its cognate peptide-MHC (pMHC), it triggers activation of a signaling cascade that results in the elicitation of a T cell effector function. Different models have been proposed to understand which parameters are needed to obtain an optimal activation of the signaling. It was speculated that improving the binding of a TcR could bring a stronger pMHC recognition, hence a stronger stimulation of the T cell. However, it was recently shown that an increase in affinity does not seem to be sufficient to guarantee improved functionality. A combination of factors is necessary to place the modified TcR in an optimal functional window. We here compared the binding parameters of two mutants of the melanoma antigen peptide MART-127 − 35 specific TcR DMF5. The first mutant was previously isolated by others in a screen for improved TcR. It was reported to have an increased CD8-independent activity. We confirmed these data and showed that the enhancement was neither due to change in half life (t1/2) nor Kd of the pMHC-TcR complex. The second mutant was designed based on a previous report claiming that a particular polymorphic residue in the TRAV12-2 chain was stabilizing the TcR. We created a DMF5 mutant for this residue and showed that, unexpectedly, this TcR had acquired a reduced overall activity although the TcR-pMHC complex was more stable when compared to the TcR wild type complex (increased t1/2). In addition, the soluble TcR form of this mutant bound target cells less efficiently. From this we concluded that kinetic parameters do not always predict the superior functionality of mutant TcRs.
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Kumari, Shraddha; Waelchli, Sebastien; Fallang, Lars-Egil; Yang, Weiwen; Lund-Johansen, Fridtjof & Schumacher, Ton N.
[Show all 7 contributors for this article]
(2014).
Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes.
Proceedings of the National Academy of Sciences of the United States of America (PNAS).
ISSN 0027-8424.
111(1),
p. 403–408.
doi:
10.1073/pnas.1306549111.
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Wälchli, Sebastien; Løset, Geir Åge; Kumari, Shraddha; Johansen, Jorunn; Yang, Weiwen & Sandlie, Inger
[Show all 7 contributors for this article]
(2011).
A Practical Approach to T-Cell Receptor Cloning and Expression.
PLOS ONE.
6(11).
doi:
10.1371/journal.pone.0027930.
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Although cloning and expression of T-cell Receptors (TcRs) has been performed for almost two decades, these procedures are still challenging. For example, the use of T-cell clones that have undergone limited expansion as starting material to limit the loss of interesting TcRs, must be weighed against the introduction of mutations by excess PCR cycles. The recent interest in using specific TcRs for cancer immunotherapy has, however, increased the demand for practical and robust methods to rapidly clone and express TcRs. Two main technologies for TcR cloning have emerged; the use of a set of primers specifically annealing to all known TcR variable domains, and 59-RACE amplification. We here present an improved 59-RACE protocol that represents a fast and reliable way to identify a TcR from 105 cells only, making TcR cloning feasible without a priori knowledge of the variable domain sequence. We further present a detailed procedure for the subcloning of TcRa and b chains into an expression system. We show that a recombination-based cloning protocol facilitates simple and rapid transfer of the TcR transgene into different expression systems. The presented comprehensive method can be performed in any laboratory with standard equipment and with a limited amount of starting material. We finally exemplify the straightforwardness and reliability of our procedure by cloning and expressing several MART-1-specific TcRs and demonstrating their functionality. © 2011 Wälchli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Published
Jan. 29, 2026 3:25 PM
- Last modified
Jan. 29, 2026 3:25 PM
