Ets1 and Rbpj Knock-Outs to Improve T Cell Function (SJ-24-0015)

St. Jude Reference #SJ-24-0015

Description

T cells are the key immune system component involved in killing cancer. Tumors produce signals that turn off these T cells, partially by forcing them to progressively differentiate (mature) into a hypofunctional state known as exhaustion. Cancer cells evade T cell-mediated killing through tumour–immune interactions, whose mechanisms are not well understood. Existing immunotherapies target precursor exhausted T (Tpex) cells for better antitumor response. However, terminal exhausted T (Tex) cells are the most abundant CD8+ T cells in tumors, but they are unresponsive to existing immunotherapies. This means there is an opportunity to identify the regulators underlying Tpex to Tex cell differentiation and identify strategies to functionally reinvigorate Tex cells.

Scientists from St. Jude Children's Research Hospital comprehensively examined the transcription factors involved in T-cell differentiation states in cancer. They then used this information to enhance anticancer activity in preclinical models by promoting or blocking T-cell differentiation. They identified two genes, Ets1 (NCBI gene ID: 23871) and Rbpj (NCBI gene ID: 19664), that could be deleted in CD8+ T cells to improve the efficacy of T cell-mediated therapies. They also identified that Ets1 or Rbpj-deficient CD8+ T cells could further enhance their antitumor effect when treated together with immune checkpoint blockade (ICB) (e.g. anti-PD-L1). Targeting Ets1 and Rbpj promotes accumulation of intermediate Tex cells and T-cell effector function by facilitating Tpex to Tex cell transition and enriching the proliferative state in Tex cells, respectively. This is useful for T cell-mediated therapies (including adoptive cell therapy and CAR T cell therapy) towards tumors, or a combination of cell therapy and ICB towards tumors.

Keywords

Solid tumor, Liquid Tumor, immunotherapy, cancer, CD8+ T cell, tumour, Dendritic cells (DCs), Tpex, Tex, Ets1 (NCBI gene ID: 23871), Rbpj (NCBI gene ID: 19664), immune checkpoint blockade (ICB), (anti–PD-1 or PD-L1).

Granted patents or published applications

Unpublished application pending.

Related scientific references

Zhou, P., Shi, H., Huang, H. et al. Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer. Nature (2023). https://doi.org/10.1038/s41586-023-06733-x

An article about the Nature paper is located here:|
Scientists identify T-cell differentiation nodes to improve cancer-killing

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