LEF1 Drives a Central Memory Program and Supports Antitumor Activity of Natural Killer T Cells

Ngai, Ho; Barragan, Gabriel A.; Tian, Gengwen; Balzeau, Julien; Zhang, Chunchao; Courtney, Amy N.; Guo, Linjie; Xu, Xin; Wood, Michael S.; Drabek, Janice; Demberg, Thorsten; Sands, Caroline M.; Chauvin, Cynthia; Pierro, Erica J. Di; Rosen, Jeffrey M.; Metelitsa, Leonid S.

doi:10.1158/2326-6066.cir-22-0333

Cited by 12 publications

(9 citation statements)

References 60 publications

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“…7g and Supplementary Table S4 ). Among them, LEF1 is required for the stemness of CD8 + T cells, 29 , 30 which may play a crucial role in maintaining the stemness subsets in IL-21R-TCR-T. Besides, our data showed elevated STAT3 transcriptional activity in IL-21R-TCR-T and corroborated the constitutive IL-21 signaling in IL-21R-TCR-T.…”

Section: Resultssupporting

confidence: 78%

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma

Zhu,

Zhang,

Chen

et al. 2024

Sig Transduct Target Ther

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Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

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Section: Resultssupporting

confidence: 78%

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma

Zhu,

Zhang,

Chen

et al. 2024

Sig Transduct Target Ther

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“…2a and Fig. S2A ), including upregulation of markers of activation/exhaustion such as PD-1 , HAVRC2 (TIM3) , LAG-3 and CTLA4 , but also markers associated with memory NKTs such as SELL (CD62L), and the transcription factor LEF1 26 . We then compared published gene signature expression scores for cellular pathways and T-cell exhaustion between IL12(I)GFP and GFP NKTs.…”

Section: Resultsmentioning

confidence: 99%

IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity

Landoni,

Woodcock,

Barragan

et al. 2024

Nat Commun

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Human natural killer T cells (NKTs) are innate-like T lymphocytes increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintains a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observe that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates a de novo programming of memory NKTs in CD62L-negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic differentiation hierarchy, and that IL-12 plays a role in promoting their differentiation to long-lived Th1-polarized memory cells. Human NKTs engineered to co-express a Chimeric Antigen Receptor (CAR) coupled with the expression of IL-12 show enhanced antitumor activity in leukemia and neuroblastoma tumor models, persist long-term in vivo and conserve the molecular signature driven by the IL-12 expression. Thus IL-12 reveals an intrinsic plasticity of peripheral human NKTs that may play a crucial role in the development of cell therapeutics.

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“…This is further supported by the rela-ve upregula-on of genes known to play important roles in iNKT cell development, including LEF1, TOX2, SATB1, SOX4, and ITM2A (Fig 1F) 16,20,[37][38][39][40] . Indeed, previous reports showed that lymphoid enhancer binding factor 1 (LEF1) expression correlated with, and appeared to regulate, CD62L expression in ex vivo expanded iNKT cells, albeit with a central memory phenotype possibly reflec-ng changes occurring during culture 41,42 . The majority of the rest of the iNKT cells in our analysis displayed an effector memory signature with no/low expression of CCR7 and CD45RA.…”

Section: Expression Paherns Reveal Unique T Effector Memory Cd45ra + ...mentioning

confidence: 99%

Single cell resolution analysis of multi-tissue derived human iNKT cells reveals novel transcriptional paradigms

Jayasinghe,

Hollingsworth,

Boonchalermvichian

et al. 2024

Preprint

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Invariant natural killer T (iNKT) cells are evolutionarily conserved innate lymphocytes important for host defense against pathogens. Further, they are increasingly recognized to play a role in tumor immune surveillance and in protection against graft versus host disease, and they are of particular importance as a universal donor for cellular therapies. Therefore, a thorough understanding of the biology of iNKT cells is critical. Murine studies have revealed the existence of transcriptionally and functionally distinct subsets, similar to T helper cell subsets. However, a comprehensive study of human iNKT cell heterogeneity is lacking. Herein, we define the transcriptomic heterogeneity of human iNKT cells derived from multiple immunologically relevant tissues, including peripheral blood, cord blood, bone marrow, and thymus, using single cell RNA-sequencing. We describe human iNKT cells with a naïve/precursor transcriptional pattern, a Th2-like signature, and Th1/17/NK-like gene expression. This combined Th1/17 pattern of gene expression differs from previously described murine iNKT subsets in which Th1- and Th17-like iNKT cells are distinct populations. We also describe transcription factors regulating human iNKT cells with distinct gene expression patterns not previously described in mice. Further, we demonstrate a novel T effector memory RA+(TEMRA)-like pattern of expression in some human iNKT cells. Additionally, we provide an in-depth transcriptional analysis of human CD8+iNKT cells, revealing cells with two distinct expression patterns, one consistent with naïve/precursor cells and one consistent with Th1/17/NK-like cells. Collectively, our data provide critical insights into the transcriptional heterogeneity of human iNKT cells, providing a platform to facilitate future functional studies and to inform the development of iNKT-based cellular therapies.

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LEF1 Drives a Central Memory Program and Supports Antitumor Activity of Natural Killer T Cells

Cited by 12 publications

References 60 publications

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma

IL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity

Single cell resolution analysis of multi-tissue derived human iNKT cells reveals novel transcriptional paradigms

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