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

• Autores: Taylor, BC, Sun, X, Gonzalez-Ericsson, PI, Sanchez, V, Sanders, ME, Wescott, EC, Opalenik, SR, Hanna, A, Chou, S-T, Van, Kaer, L, Gomez, H, Isaacs, C, Ballinger, TJ, Santa-Maria, CA, Shah, PD, Dees, EC, Lehmann, BD, Abramson, VG, Pietenpol, JA, Balko, JM
• Formato: artículo
• Fecha de Publicación: 2024
• Institución: Instituto Nacional de Enfermedades Neoplásicas
• Repositorio: INEN-Institucional
• Lenguaje: inglés
• OAI Identifier: oai:repositorio.inen.sld.pe:20.500.14703/401
• Enlace del recurso: https: //doi.org/10.1158/2159-8290.CD-23-0519; https://hdl.handle.net/20.500.14703/401
• Nivel de acceso: acceso abierto
• Materia: alpha2 integrin; anti PD L1 antibody; atezolizumab; carboplatin; CXCL9 chemokine; cytokeratin; gamma interferon; gamma interferon inducible protein 10; human leukocyte antigen -A B C; immune checkpoint inhibitor; immunoglobulin G antibody; interleukin 2; leukocyte antigen; natural killer cell receptor NKG2A; programmed death 1 ligand 1; unclassified drug; https://purl.org/pe-repo/ocde/ford#3.02.21

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell–directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti–PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti–PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance.