Fibroblast-derived LPP as a biomarker for treatment response and therapeutic target in gastric cancer

Association of tumor microenvironment and immune checkpoint (e.g., PD-L1) is important for immune escape, impacting chemotherapy and immunotherapy efficacy. We aimed to investigate biomarkers and therapeutic targets against treatment resistance in gastric cancer. Abundances of tumor-infiltrating immune cells were estimated in multiple datasets. Three patient subgroups (A, B, and C) were identified based on seven types of PD-L1- and IFN-γ-associated immune cells. Patients yielded increased prognosis from subgroup A to C (p = 0.027). Subgroup A was characterized by high activated CD4⁺ memory T cell infiltration, while more resting CD4⁺ memory T cells were in subgroup C. Further, a risk score was developed for prognostication. Lipoma preferred partner (LPP), as the hub gene in subgroup-related regulatory network, was upregulated (p < 0.01) and was associated with high risk score (p < 0.001) and poor survival (p < 0.05). Bioinformatics analyses and experiments found that LPP expressed restrictively in fibroblasts and associated with activated CD4⁺ memory T cell infiltration and tumor growth. High-LPP patients yielded fewer benefits from chemotherapy or immunotherapy, compared with the low-LPP group. We finally identified 28 compounds as sensitive drugs for high-LPP patients. Our findings suggested LPP might be a biomarker for treatment response and therapeutic target in gastric cancer.