Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Immunotherapies targeting the PD-1 pathway offer durable responses in various cancers.
• Tumor-intrinsic factors influencing response and resistance to these therapies remain largely unknown.
• MHC-II expression on tumor cells is a known predictor of response to anti-PD-1 therapy.

Purpose of the Study:

• To elucidate how MHC-II expression by tumor cells drives dependency on PD-1.
• To investigate the immune microenvironment of MHC-II+ tumors in response to anti-PD-1 therapy.
• To identify novel targets for overcoming adaptive resistance to PD-1 blockade.

Main Methods:

• Transcriptional profiling of patients treated with anti-PD-1 therapy.
• Analysis of immune cell infiltration in MHC-II+ tumors.
• Evaluation of receptor expression (Lag-3, FCRL6) in preclinical models and patient samples.
• Functional assessment of FCRL6 in the tumor microenvironment.

Main Results:

• MHC-II+ tumors exhibit distinct immune activation patterns and recruit CD4+ T cells.
• MHC-II+ tumors demonstrate dependency on PD-1 and upregulation of Lag-3 upon acquired resistance to anti-PD-1 therapy.
• Enhanced expression of FCRL6, an MHC-II receptor, was observed in the microenvironment of MHC-II+ tumors, suggesting a novel inhibitory role.

Conclusions:

• MHC-II expression on tumor cells creates a context that promotes PD-1 dependency and adaptive resistance.
• Lag-3 and FCRL6 emerge as potential therapeutic targets in MHC-II+ tumors resistant to anti-PD-1 therapy.
• These findings reveal an MHC-II-mediated mechanism contributing to immunotherapy resistance, offering new avenues for treatment optimization.