PD-1-cis IL-2R agonism yields better effectors from stem-like CD8⁺ T cells

Area of Science:

• Immunology
• Cancer Biology
• Virology

Background:

• Antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells are crucial for PD-1 blockade immunotherapy success.
• Interleukin (IL)-2 promotes stem-like T cell differentiation into 'better effector' CD8+ T cells, but CD25 binding causes systemic effects.
• Engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists aim to mitigate these side effects.

Purpose of the Study:

• To evaluate IL-2Rβγ-biased agonists for expanding 'better effector' T cells in cancer models.
• To introduce PD1-IL2v, a novel immunocytokine designed for cis-targeting PD-1 and IL-2Rβγ.
• To assess PD1-IL2v's efficacy in differentiating stem-like CD8+ T cells and treating chronic infections and cancer.

Main Methods:

• Development and testing of PD1-IL2v, a PD-1 cis-targeted IL-2 variant.
• Assessment of T cell differentiation and expansion in chronic infection and cancer models.
• Comparison of PD1-IL2v with PD-1/PD-L1 blocking antibodies and non-targeted IL-2 variants.

Main Results:

• IL-2Rβγ-biased agonists failed to preferentially expand 'better effector' T cells in cancer models.
• PD1-IL2v successfully differentiated stem-like CD8+ T cells into 'better effectors' without CD25 binding, showing superior efficacy in chronic infection and cancer models.
• PD-1/PD-L1 blockade with non-targeted IL-2 variants led to exhausted T cell accumulation, unlike PD1-IL2v.

Conclusions:

• PD1-IL2v overcomes CD25 dependency, enabling targeted expansion of 'better effector' CD8+ T cells.
• This new generation of PD-1 cis-targeted IL-2R agonists offers enhanced therapeutic potential for cancer and chronic infections.
• PD1-IL2v represents a promising strategy to improve immunotherapy outcomes by generating effective anti-tumor and anti-viral T cell responses.