TY  - JOUR
AU  - Stadler, Serena
AU  - Blasco, Rafael B
AU  - Singh, Vijay Kumar
AU  - Damm-Welk, Christine
AU  - Ben-Hamza, Amin
AU  - Welters, Carlotta
AU  - Hansmann, Leo Alexander
AU  - Chiarle, Roberto
AU  - Woessmann, Wilhelm
TI  - Endogenous CD4+ T Cells That Recognize ALK and the NPM1::ALK Fusion Protein Can Be Expanded from Human Peripheral Blood.
JO  - Cancer immunology research
VL  - 13
IS  - 4
SN  - 2326-6066
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2025-00683
SP  - 487 - 495
PY  - 2025
AB  - Anaplastic lymphoma kinase (ALK) fusion proteins resulting from chromosomal rearrangements are promising targets for cancer immunotherapy. Although ALK-specific CD8+ T cells and epitopes presented on MHC class I have been identified in patients with ALK-positive malignancies, little is known about ALK-specific CD4+ T cells. We screened peripheral blood of 10 patients with ALK-positive anaplastic large-cell lymphoma in remission and six healthy donors for CD4+ T-cell responses to the whole ALK fusion protein, nucleophosmin 1 (NPM1)::ALK. ALK-specific CD4+ T cells were detected in 15 individuals after stimulation with autologous dendritic cells pulsed with long-overlapping ALK peptide pools. CD4+ T-cell epitopes were predominantly located within three specific regions (p102-188, p257-356, and p593-680) in the ALK portion of the fusion protein. We detected CD4+ T cells in one patient that recognized the NPM1::ALK fusion neoepitope and identified a corresponding T-cell receptor (TCR) by TCRαβ single-cell sequencing. The NPM1::ALK fusion-specific TCR was HLA-DR13-restricted and conferred antigen specificity when expressed in a TCR- reporter cell line (58α-β-). Together, our data provide evidence of ALK-specific CD4+ T cells in human peripheral blood, describe target epitopes in patients, and support the consideration of CD4+ T cells in the development of ALK-specific immunotherapies.
KW  - Humans
KW  - Nucleophosmin
KW  - CD4-Positive T-Lymphocytes: immunology
KW  - CD4-Positive T-Lymphocytes: metabolism
KW  - Nuclear Proteins: genetics
KW  - Nuclear Proteins: immunology
KW  - Oncogene Proteins, Fusion: genetics
KW  - Oncogene Proteins, Fusion: immunology
KW  - Anaplastic Lymphoma Kinase: genetics
KW  - Anaplastic Lymphoma Kinase: immunology
KW  - Epitopes, T-Lymphocyte: immunology
KW  - Female
KW  - Lymphoma, Large-Cell, Anaplastic: immunology
KW  - Lymphoma, Large-Cell, Anaplastic: genetics
KW  - Male
KW  - Middle Aged
KW  - Adult
KW  - Nucleophosmin (NLM Chemicals)
KW  - NPM1 protein, human (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - Oncogene Proteins, Fusion (NLM Chemicals)
KW  - Anaplastic Lymphoma Kinase (NLM Chemicals)
KW  - Epitopes, T-Lymphocyte (NLM Chemicals)
KW  - ALK protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39774774
DO  - DOI:10.1158/2326-6066.CIR-24-0445
UR  - https://inrepo02.dkfz.de/record/300221
ER  -