Multi-omics analysis reveals the role of tumor-infiltrating CD4+CCR7+ T cells in EGFR antibody resistance and prognosis of hepatocellular carcinoma

Background Despite the crucial involvement of the EGFR pathway in hepatocellular carcinoma (HCC), the clinical efficacy of EGFR antibodies in HCC remains uncertain. While existing evidence suggests that immune dysfunction and tumor microenvironment alterations may contribute to treatment resistance, the precise mechanisms underlying this phenomenon in HCC warrant further investigation. Methods In this study, we employed patient-derived xenograft (PDX) models generated from 14 HCC patients enrolled in the REHOPE301 cohort to evaluate the sensitivity to nimotuzumab, a humanized anti-EGFR monoclonal antibody. Whole-exome sequencing (WES) and single-cell RNA sequencing were performed on tumor tissues and tumor-infiltrating lymphocytes (TILs) to elucidate the association between TIL characteristics and EGFR antibody response. A predictive risk score and nomogram were subsequently developed using LASSO regression analysis. The prognostic performance of this model was evaluated using 2 external datasets (ICGC-JP and GSE141202) through receiver operator characteristic (ROC) curves and calibration curves analyses. Results Nimotuzumab demonstrated a 50% response rate (7/14) in PDX models. Immune profiling revealed distinct TIL patterns between responders and non-responders. Notably, CD4 ⁺ CCR7 ⁺ T cells were significantly enriched in resistant tumors (p < 0.001) and negatively correlated with the nimotuzumab response (r = -0.767 p = 0.02). In non-responsive tumors, CD4 ⁺ CCR7 ⁺ T cells exhibited interactions with macrophages and CD8 ⁺ PDCD1 ⁺ T cells. A reduced infiltration of CD4 ⁺ CCR7 ⁺ T cells was associated with improved prognosis and enhanced EGFR antibody efficacy across multiple cancer types. Furthermore, a nine-gene signature related to CD4 ⁺ CCR7 ⁺ T cells was identified as a strong prognostic factor in HCC (HR = 5.19, 95% CI: 3.18–8.46, P < 0.001), and was used to construct a nomogram. WES confirmed prognostic gene mutations (VCAN, CAMK4, and CD226) potentially influencing nimotuzumab response. Conclusions Our findings indicate that increased infiltration of central memory CD4 ⁺ CCR7 ⁺ T cells in HCC may reflect an immunosuppressive tumor microenvironment, thereby impairing EGFR antibody efficacy and worsening patient prognosis.