TY - JOUR

T1 - Decoding NY-ESO-1 TCR T cells: transcriptomic insights reveal dual mechanisms of tumor targeting in a melanoma murine xenograft model

AU - Alsalloum, Alaa

AU - Alrhmoun, Saleh

AU - Perik-Zavosdkaia, Olga

AU - Fisher, Marina

AU - Volynets, Marina

AU - Lopatnikova, Julia

AU - Perik-Zavodskii, Roman

AU - Shevchenko, Julia

AU - Philippova, Julia

AU - Solovieva, Olga

AU - Zavjalov, Evgenii

AU - Kurilin, Vasily

AU - Shiku, Hiroshi

AU - Silkov, Alexander

AU - Sennikov, Sergey

N1 - The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was founded by the Russian Science Foundation, project number 21-65-00004.

PY - 2024/1

Y1 - 2024/1

N2 - The development of T cell receptor-engineered T cells (TCR-T) targeting intracellular antigens is a promising strategy for treating solid tumors; however, the mechanisms underlying their effectiveness remain poorly understood. In this study, we employed advanced techniques to investigate the functional state of T cells engineered with retroviral vectors to express a TCR specific for the NY-ESO-1 157-165 peptide in the HLA-A*02:01 context. Flow cytometry revealed a predominance of naïve T cells. Gene expression profiling using NanoString technology revealed upregulation of genes encoding chemokine receptors CCR2 and CCR5, indicating enhanced migration towards tumor sites. In the SK-Mel-37 xenograft model, these transduced T cells achieved complete tumor eradication. Furthermore, single-cell RNA sequencing (scRNA-seq) conducted 14 days post-TCR T cell infusion provided a comprehensive analysis of the in vivo adaptation of these cells, identifying a distinct subset of CD8+ effector T cells with an NK cell-like gene expression profile. Our findings indicate that NY-ESO-1 TCR-transduced T cells have the potential to mediate dual antitumor effects through both antigen-independent NK-like and antigen-specific CTL-like responses. This study underscores the potential of NY-ESO-1 TCR-T cells as potent tumor-eradicating agents, highlighting the importance of harnessing their versatile functional capabilities to refine and enhance therapeutic strategies.

AB - The development of T cell receptor-engineered T cells (TCR-T) targeting intracellular antigens is a promising strategy for treating solid tumors; however, the mechanisms underlying their effectiveness remain poorly understood. In this study, we employed advanced techniques to investigate the functional state of T cells engineered with retroviral vectors to express a TCR specific for the NY-ESO-1 157-165 peptide in the HLA-A*02:01 context. Flow cytometry revealed a predominance of naïve T cells. Gene expression profiling using NanoString technology revealed upregulation of genes encoding chemokine receptors CCR2 and CCR5, indicating enhanced migration towards tumor sites. In the SK-Mel-37 xenograft model, these transduced T cells achieved complete tumor eradication. Furthermore, single-cell RNA sequencing (scRNA-seq) conducted 14 days post-TCR T cell infusion provided a comprehensive analysis of the in vivo adaptation of these cells, identifying a distinct subset of CD8+ effector T cells with an NK cell-like gene expression profile. Our findings indicate that NY-ESO-1 TCR-transduced T cells have the potential to mediate dual antitumor effects through both antigen-independent NK-like and antigen-specific CTL-like responses. This study underscores the potential of NY-ESO-1 TCR-T cells as potent tumor-eradicating agents, highlighting the importance of harnessing their versatile functional capabilities to refine and enhance therapeutic strategies.

KW - NY-ESO-1

KW - SK-Mel-37

KW - TCR T cells

KW - adoptive transfer

KW - cancer-testis antigen

KW - mice model

KW - transcriptomics

KW - xenograft

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85211211459&origin=inward&txGid=2f6bb177a88dd6db6de021b80bb3188c

UR - https://www.mendeley.com/catalogue/7e7a0bed-9e8a-3bd0-b0bf-9ee7f54b5b44/

U2 - 10.3389/fimmu.2024.1507218

DO - 10.3389/fimmu.2024.1507218

M3 - Article

C2 - 39660132

VL - 15

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 1507218

ER -