The Immune Signatures Predict Gastric/Gastroesophageal Junction Cancer Response to First-line Anti-PD-1 Blockade or Chemotherapy: Clinical and Multiplex Immunofluorescence Analysis

Background Anti-PD-1 immunotherapy and platinum-based chemotherapy are key components of first-line treatment for advanced Gastric or Gastroesophageal Junction Cancer (G/GEJ). However, the role of immune cells infiltrating the tumor microenvironment in predicting both therapy responses is still unclear. Methods We performed exploratory analyses of progression-free survival(PFS) and overall survival (OS) based on PD-L1 expression and a landmark statistical method, and developed a multiplexed immunofluorescence assay for CD4, CD8, PD-L1, CD68 and FoxP3 coupled with digital image analysis and machine learning to assess prognostic survival associations of immune cells. Results For patients with PD-L1 CPS < 10, greater disparities in survival between anti-PD-1 immunotherapy and chemotherapy were shown around 300 days after treatment. High expression of PD-L1 was associated with longer survival when receiving anti-PD-1 blockade, but showed less benefit when receiving platinum-based chemotherapy by subgroup analysis. The analysis of mIF also demonstrated significantly higher stromal density of PD-L1 in the well-responder group of patients receiving immunotherapy than the poor-response group, but tended to be lower in patients receiving chemotherapy. Besides, we found that high tumor stromal density of CD8 could be used as a biomarker of good prognosis in anti-PD-1 immunotherapy, and high tumor stromal density of CD4 was found to be associated with worse prognosis in platinum-based chemotherapy. Conclusions These findings indicate that increased PD-L1 expression was associated with an increased effect on anti-PD-1 immunotherapy and reduced benefit from chemotherapy. The signature of TME immune cells has the potential to predict the response of anti-PD-1 immunotherapy and chemotherapy in G/GEJ cancer.