Immune Reprogramming of Tumor Microenvironments by Cytotoxic Antibody-Drug Conjugate Payloads

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Antibody-drug conjugates (ADCs) are effective cancer treatments, but their effects on the tumor microenvironment (TME) are not fully understood.
• Understanding ADC-induced TME changes is crucial for optimizing cancer therapy.

Purpose of the Study:

• To investigate the distinct impacts of two HER2-targeting ADCs, T-MMAE and T-DXd, on the TME.
• To compare the immunomodulatory effects of different ADC payloads on tumor-infiltrating immune cells.

Main Methods:

• Utilized an immunocompetent murine model expressing human HER2.
• Evaluated T-MMAE and T-DXd, assessing immune cell infiltration, myeloid cell phenotypes, and anti-tumor responses.
• Combined ADCs with anti-PD-1 immunotherapy.

Main Results:

• T-MMAE increased immune cell infiltration, particularly macrophages with specific gene expression profiles.
• T-DXd reduced immune cell infiltration but enhanced CD80 expression on antigen-presenting cells (APCs).
• Both ADCs, when combined with anti-PD-1, showed additive anti-tumor effects and induced immunological memory via CD8+ T cells.

Conclusions:

• Different ADC payloads induce distinct immunological responses within the TME, influencing myeloid cell activation.
• These findings highlight the importance of considering payload-specific TME modulation for ADC-based cancer therapy.