Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Immune checkpoint blockade, particularly PD-1/PD-L1 blockade, shows promise for advanced cancers but benefits only a subset of patients.
• Inefficient T cell activation is a potential reason for the limited efficacy of current immunotherapies.

Purpose of the Study:

• To investigate if targeting interleukin-21 (IL-21) to tumor-reactive T cells can enhance anti-tumor immune responses.
• To develop a novel fusion protein combining IL-21 with an anti-PD-1 antibody for improved cancer therapy.

Main Methods:

• Fusion of IL-21 to an anti-PD-1 antibody to create a targeted delivery system (PD-1Ab21).
• Evaluation of PD-1Ab21's effect on T cell populations, specifically memory stem T cells (T_SCM), and their proliferation.
• Assessment of PD-1Ab21's antitumor efficacy in established tumor-bearing mouse models.

Main Results:

• The fusion protein PD-1Ab21 successfully promoted the generation of T_SCM with enhanced proliferation.
• PD-1Ab21 treatment demonstrated potent antitumor effects in mice.
• Increased frequency of T_SCM and expansion of tumor-specific CD8+ T cells with a memory phenotype were observed.
• PD-1Ab21 therapy was superior to the combination of PD-1 blockade and IL-21 infusion.

Conclusions:

• Targeting IL-21 to tumor-reactive T cells via antibody fusion is a viable strategy to enhance T cell function.
• This approach improves the generation of memory stem T cells and boosts antitumor immunity.
• Simultaneously targeting cytokines to tumor-reactive T cells represents a promising strategy to improve immune checkpoint blockade therapy.