Journal Article

An engineered IL-2 partial agonist promotes CD8+ T cell stemness

Leonard, Warren J., Restifo, Nicholas P., Ren, Min, Lin, Jian-Xin, Yamamoto, Tori N., Oh, Jangsuk, Powell, Jonathan D., Mo, Fei, Liao, Wei, Hermans, Dalton, Gattinoni, Luca, Garcia, K. Christopher, Zhuang, Xiaoxuan, Yu, Zhiya, Glassman, Caleb R., Zhao, Liang, Chen, Yun, Mitra, Suman, Li, Peng, Majri-Morrison, Sonia, Golebiowski, Filip M., Spolski, Rosanne, Picton, Lora K.

2021

Overview

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients 1 . Both the number of transferred T cells and their differentiation state are critical determinants of effective responses 2 , 3 . T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells 4 , 5 and lower therapeutic efficacy 6 , whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial 7 . Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8 +  T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8 + T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential. H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/21 / 13/95 / 45 / 45/15 / 45/23 / 631/250/127 / 631/250/580 / 64/60 / Acute lymphoblastic leukemia / Adoptive transfer / Agonists / Animal models / Animals / Anticancer properties / Antigens / Cancer immunotherapy / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Cell differentiation / Cell Differentiation - drug effects / Chimeric antigen receptors / Cytokines / Drug Partial Agonism / Effector cells / Epigenetics / Genes / Glucose / Hepatocyte nuclear factor 1 / Humanities and Social Sciences / Immunotherapy / Interleukin 2 / Interleukin-2 - agonists / Interleukin-2 - analogs & derivatives / Interleukin-2 - chemistry / Interleukin-2 - genetics / Leukemia / Lymphocytes / Lymphocytes T / Maintenance / Melanoma / Melanoma - metabolism / Metabolism / Mice / Mitochondria / Mitochondria - drug effects / multidisciplinary / Mutant Proteins - chemistry / Mutant Proteins - genetics / Mutant Proteins - pharmacology / Mutation / Phosphorylation / Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Receptors / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - metabolism / Robustness / Science / Science (multidisciplinary) / Stat5 protein / STAT5 Transcription Factor - metabolism / Stem cells / Stem Cells - cytology / Stem Cells - drug effects / T cell receptors / T Cell Transcription Factor 1 - metabolism / Transcription factors / Translational Research, Biomedical / Tumors