Effect of branched-chain amino acid metabolic interactions between HIBADH+ tumor cells and BCAT1+ macrophages on immunotherapy response in advanced NSCLC.

Abstract

e20601 Background: Tumor immune checkpoint inhibitors (ICIs) have been established as the first-line standard treatment for advanced NSCLC with negative driver genes. However, only approximately 20% to 30% of patients truly benefit from ICI treatment in the long term. Meanwhile, an increasing number of studies have focused on the amino acid metabolic reprogramming of tumor cells, especially the impact of branched-chain amino acid (BCAA) metabolism on the phenotypic and functional changes of tumor-infiltrating immune cells and its influence on the immunotherapy response. Therefore, we aim to explore the impact of BCAA metabolic reprogramming in tumor cells on the immunotherapy response in advanced NSCLC and develop novel immunotherapy combination regimens to reverse the short survival benefit. Methods: We collected lung tissue samples from patients with long (PFS≥12 months) and short (PFS≤3 months) term response from immunotherapy for transcriptomic and single-cell sequencing to analyze cell subtypes and metabolic pathways. Changes in microenvironmental indicators were verified by multiplex fluorescence immunohistochemistry. We elucidated the interaction mechanisms between cells through co-culture experiments and constructed animal models to explore novel combined immunotherapy regimens. Results: The results of transcriptome and single-cell differential analysis showed that the BCAA metabolic pathway was most significantly upregulated in the short term response samples. BCAT1+ macrophages and HIBADH+ tumor cells were significantly upregulated in the short term response samples and had certain BCAA metabolism interaction. Through co-culture experiments of cells, we innovatively found that HIBADH+ tumor cells utilize BCAA for their energy supply and secrete vesicles to transport metabolic enzymes to stimulate the upregulation of BCAT1 expression in macrophages. BCAT1+ macrophages reverse-synthesize BCAA in response to vesicle stimulation and accumulate α-KG, exhibiting an immunosuppressive phenotype and could inhibit the proliferation and effector function of cytotoxic T cells. The reverse-synthesized BCAA and α-KG are reused by tumor cells for their own proliferation needs. Animal experiments showed that targeting BCAA metabolism combined with immunotherapy could help enhance the survival benefit of immunotherapy. Conclusions: HIBADH+ tumor cells secrete vesicles to transport metabolic enzymes to stimulate the upregulation of BCAT1 expression in macrophages. BCAT1+ macrophages reverse-synthesize BCAA under the stimulation of vesicles and mediate the accumulation of α-KG, showing an immunosuppressive phenotype and resulting in short term response of immunotherapy for advanced NSCLC. Targeting BCAA metabolism combined with immunotherapy may be a novel immunotherapy combination regimen.