NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Immune checkpoint inhibition (ICI) shows promise in cancer treatment, but resistance, particularly in triple-negative breast cancer (TNBC), remains a challenge.
• MHC-I expression is crucial for antigen presentation and T-cell-mediated immunotherapy.
• Intratumor heterogeneity in MHC-I expression is observed in TNBC patients.

Purpose of the Study:

• To investigate the role of MHC-I expression heterogeneity in driving resistance to immunotherapy in TNBC.
• To identify potential therapeutic strategies to overcome immunotherapy resistance in TNBC.

Main Methods:

• Analysis of intratumor MHC-I expression heterogeneity in TNBC patients.
• Utilized murine models to study the impact of MHC-I loss and heterogeneity on antitumor immunity and ICI response.
• Employed spatial technologies to correlate MHC-I heterogeneity with clinical resistance to anti-PD-L1 therapy and NK:T-cell ratios in human breast tumors.
• Investigated the role of NKG2A in suppressing NK-cell function in MHC-I heterogeneous tumors.

Main Results:

• Loss of MHC-I in murine models abrogated antitumor immunity and ICI response.
• Intratumor MHC-I heterogeneity promoted NK cell infiltration in an IFNγ-dependent manner.
• MHC-I heterogeneity in human breast tumors correlated with resistance to anti-PD-L1 therapy and increased NK:T-cell ratios.
• MHC-I heterogeneous tumors relied on NKG2A to inhibit NK cell activity.

Conclusions:

• Heterogeneous MHC-I expression is a key mechanism of clinical resistance to anti-PD-L1 therapy in TNBC.
• Combining anti-NKG2A and anti-PD-L1 therapies restored complete response in preclinical models of MHC-I heterogeneous TNBC.
• This combination strategy holds promise for enhancing patient benefit in clinical trials for TNBC.