Tissue-specific tumor microenvironments influence responses to immunotherapies

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Variable response rates to cancer immunotherapies are linked to the immunosuppressive tumor microenvironment (TME).
• Tumor location is a key determinant of TME composition and immunotherapy response.
• Existing preclinical models lack clinical relevance for studying tissue-specific TMEs.

Purpose of the Study:

• To investigate the impact of tissue-specific tumor microenvironments (TMEs) on immunotherapy response.
• To compare responses to αPD-1/αCTLA4 and trimAb therapies in clinically relevant metastatic sites (liver and lungs).

Main Methods:

• Utilized 67NR mouse breast cancer and Renca mouse kidney cancer models.
• Assessed TMEs and therapy responses in tumors located in the lungs, liver, mammary fat pad (MFP), and subcutaneously.
• Analyzed immune cell infiltration, activation, and drug delivery in different tumor locations.

Main Results:

• Lung tumors were resistant to αPD-1/αCTLA4 and trimAb therapies, while tumors in MFP, liver, and subcutaneously were eradicated.
• Lung tumors exhibited a more immunosuppressive TME with increased myeloid-derived suppressor cells and decreased T and NK cell activity.
• NK cells and CD8+ T cells play equivalent roles in lung tumor control, but targeting them was insufficient for robust response.

Conclusions:

• Tissue-specific TMEs significantly influence cancer immunotherapy outcomes.
• Understanding and defining site-specific response patterns is crucial for improving patient treatment strategies.