CD73 expression on effector T cells sustained by TGF-β facilitates tumor resistance to anti-4-1BB/CD137 therapy

Area of Science:

• Immunology
• Cancer Biology
• Molecular Medicine

Background:

• Agonist antibodies targeting costimulatory molecules like 4-1BB (CD137) are under investigation for cancer immunotherapy.
• Their therapeutic efficacy as single agents is often limited, and mechanisms of action require further elucidation.
• Understanding resistance mechanisms is crucial for optimizing these immunotherapies.

Purpose of the Study:

• To investigate the role of ecto-enzyme CD73 in the efficacy of agonistic anti-4-1BB antibody therapy.
• To identify mechanisms by which tumors develop resistance to anti-4-1BB therapy.
• To explore strategies for enhancing anti-4-1BB therapy through modulation of CD73 and the tumor microenvironment.

Main Methods:

• Utilized mouse models of cancer.
• Administered agonistic anti-4-1BB antibodies and anti-CD73 neutralizing antibodies.
• Analyzed T cell responses, including CD73 expression on CD8+ T cells.
• Investigated the impact of TGF-β blockade on CD73 expression and therapy response.

Main Results:

• Anti-4-1BB therapy preferentially activates CD73-negative effector T cells for tumor inhibition.
• Neutralizing CD73 enhances anti-tumor T cell immunity and improves anti-4-1BB therapy.
• The tumor microenvironment, rich in TGF-β, sustains CD73 expression on infiltrating CD8+ T cells, conferring resistance.
• TGF-β blockade downregulates CD73 on T cells, sensitizing tumors to anti-4-1BB therapy.

Conclusions:

• Ecto-enzyme CD73 plays an inhibitory role in agonistic anti-4-1BB antibody therapy.
• CD73 expression on T cells, sustained by tumor-derived TGF-β, is a key mechanism of resistance.
• Combining anti-4-1BB therapy with CD73 blockade or TGF-β blockade represents a promising strategy to enhance anti-tumor immunity and clinical outcomes.