This study is the first to reveal the predictive value of B7H3 in resistance to combination therapy with anti-LAG3 and anti-PD1, providing crucial biomarker clues for personalized neoadjuvant treatment strategies in melanoma.
Literature Overview
The article titled 'Long-term survival & biomarker analysis evaluating neoadjuvant plus adjuvant relatlimab (anti-LAG3) and nivolumab (anti-PD1) in patients with resectable melanoma,' published in the Journal of Clinical Oncology, systematically investigates the long-term efficacy and biomarker characteristics of combination neoadjuvant therapy using anti-LAG3 (relatlimab) and anti-PD1 (nivolumab) in patients with resectable stage III/IV melanoma. The study updates survival data with a median follow-up of 47 months and identifies gene expression signatures associated with pathological response and resistance through transcriptomic analysis, particularly highlighting a significant correlation between upregulation of B7H3 and poor treatment response.Background Knowledge
Melanoma is a highly aggressive skin tumor. Although immune checkpoint inhibitors such as PD-1 and CTLA-4 blockade have significantly improved outcomes for advanced patients, a substantial proportion still experience recurrence or develop resistance. Currently, LAG-3, as an emerging immune checkpoint target, has demonstrated superior progression-free survival compared to monotherapy when combined with PD-1 inhibition in advanced melanoma. However, in resectable cases, while neoadjuvant immunotherapy can improve pathological response rates, effective predictive biomarkers for patient selection remain lacking. The current research bottleneck lies in: how to identify patients with primary resistance to the anti-LAG3 + anti-PD1 combination? And how to overcome the T-cell exhausted tumor microenvironment? This study longitudinally collected pre- and post-operative tissue samples and performed gene expression profiling using the Nanostring nCounter PanCancer Immune 360 panel, systematically exploring gene expression signatures associated with MPR (major pathological response). It found that inflammatory pathways such as IFN-γ and TIGIT were significantly upregulated in MPR patients, whereas B7H3 (CD276) was highly expressed in non-MPR patients, suggesting its potential role as a resistance-driving factor and a promising therapeutic target.
Research Methods and Experiments
This study is based on a multicenter phase II clinical trial (NCT02519322) that enrolled 30 patients with clinical stage III/IV resectable melanoma who received two cycles of neoadjuvant nivolumab (480 mg) and relatlimab (160 mg), followed by surgery and up to 10 cycles of adjuvant therapy. The primary endpoint was pathological response, defined as ≤10% viable tumor (MPR). Long-term outcomes including 4-year event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS) were assessed. Preoperative tissue samples were collected from all patients, with some also providing postoperative specimens. Gene expression profiling (GES) was performed using the Nanostring nCounter PanCancer IO360 platform. Differential expression analysis compared MPR versus non-MPR groups, and ROC curves were used to evaluate the predictive power of individual gene signatures for MPR. Additionally, the relationships between TIGIT and B7H3 expression levels and EFS were further analyzed.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides critical long-term follow-up data for neoadjuvant immunotherapy in melanoma, confirming the durable efficacy of the anti-LAG3 + anti-PD1 regimen. More importantly, it is the first to identify B7H3 as a strong predictor of resistance to anti-PD1/anti-LAG3 therapy in a clinical cohort, suggesting it may mediate immune escape mechanisms. This finding opens new avenues for developing combination strategies to overcome resistance, such as B7H3-targeted antibody-drug conjugates or CAR-T therapies. Meanwhile, TIGIT as a response biomarker could help optimize patient selection and prevent overtreatment in those unlikely to respond.
Conclusion
This study establishes the long-term clinical value of nivolumab combined with relatlimab in patients with resectable stage III/IV melanoma, achieving an 80% 4-year EFS and indicating very low recurrence risk among MPR patients. More importantly, through systematic transcriptomic analysis, it reveals a dual-biomarker model in which B7H3 acts as a key driver of resistance and TIGIT serves as a predictive marker of response. This discovery not only offers a potential tool for prognostic stratification but also points to future therapeutic directions—targeting B7H3 may reverse resistance to dual immune checkpoint blockade. From bench to bedside, this study lays the foundation for building a more precise neoadjuvant treatment pathway in melanoma, advancing personalized immunotherapy into an era driven by biomarkers. Future validation in larger cohorts is needed, along with exploration of the clinical feasibility of B7H3-targeted combination regimens to further improve cure rates.
