Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• Checkpoint blockade therapies targeting CTLA-4 and PD-1 have advanced cancer treatment.
• Combining immunomodulatory agents may enhance antitumor responses compared to monotherapy.

Purpose of the Study:

• To investigate the efficacy of combining interleukin-21 (IL-21) with checkpoint blockade (anti-PD-1 and anti-CTLA-4) in syngeneic mouse tumor models.
• To assess the immunomodulatory effects and therapeutic potential of IL-21 in combination cancer immunotherapy.

Main Methods:

• Mice with established tumors received recombinant mouse IL-21 (mIL-21) alone or combined with monoclonal antibodies against mouse PD-1 or CTLA-4.
• Tumor growth inhibition and immune cell infiltration (CD8+ T cells) were analyzed.
• In vivo CD8+ T cell depletion was used to confirm the role of these cells.

Main Results:

• Combination therapy of IL-21 with anti-CTLA-4 mAb enhanced antitumor activity in four models, and with anti-PD-1 mAb in two models.
• Synergistic effects were observed in the EMT-6 and MC38 models for one or both combination treatments.
• Enhanced efficacy correlated with increased intratumoral CD8+ T cells, proliferation, and effector memory cells, while central memory cells decreased.

Conclusions:

• Combination of IL-21 with CTLA-4 or PD-1 blockade demonstrates significant antitumor activity and synergy in preclinical models.
• The enhanced efficacy is mediated by CD8+ T cell responses, indicating their crucial role in the combination therapy's success.
• These findings support the potential of combining recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies for improved cancer patient outcomes.