Antigen spreading mediates heterogeneous solid tumor eradication by DNA demethylating agent-programmed CAR T cells

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Antigen heterogeneity in solid tumors limits chimeric antigen receptor-modified T (CAR T) cell therapy efficacy.
• CAR T cell therapy has shown success in hematologic malignancies but faces challenges in solid tumors.

Purpose of the Study:

• To evaluate the antitumor activity of low-dose decitabine-primed CAR T (dCAR T) cells in solid tumor models.
• To investigate the mechanisms underlying dCAR T cell efficacy, including tumor microenvironment modulation and immune cell activation.

Main Methods:

• Utilized low-dose decitabine to prime CAR T cells (dCAR T cells).
• Assessed dCAR T cell efficacy in immunocompetent mice with mixed antigen-positive and antigen-negative solid tumors.
• Analyzed tumor microenvironment changes, cytokine production (interferon-γ), and immune cell responses (conventional dendritic cells, endogenous CD8+ T cells).

Main Results:

• dCAR T cell infusion effectively eliminated mixed solid tumors without prior lymphodepletion.
• Proinflammatory remodeling of the tumor immunosuppressive microenvironment was observed.
• Antigen-activated dCAR T cells produced high levels of interferon-γ, inducing immunogenic cell death and activating dendritic cells.
• This activation stimulated endogenous CD8+ T cells, enhancing antigen spreading and clearing antigen-negative tumors.

Conclusions:

• dCAR T cells demonstrate potent antitumor activity against solid tumors, even those with antigen heterogeneity.
• The mechanism involves reprogramming the tumor microenvironment and stimulating endogenous anti-tumor immunity.
• dCAR T cells exhibit robust antigen-spreading capabilities, highlighting their clinical potential for treating solid tumors.