Prognostic immune markers in esophageal cancer patients managed with trimodal therapy.

Background: Esophageal cancer (ESC) is an aggressive disease which often presents at an advanced stage. Despite trimodal therapy, 40-50% patients can develop metastatic disease by 18 months. Identification of patients at risk for metastatic spread is challenging with need for improved prognostication. We investigated whether the immune landscape of pretreatment tissue was associated with relapse in ESC patients.

Methods: Between April 2010 and October 2018, we identified 25 patients who had undergone trimodal therapy for ESC and had pretreatment biopsies suitable for analyses. We performed high-throughput multispectral immunofluorescence (mIF) analysis on formalin-fixed paraffin embedded biopsy samples. Analysis of 27 unique populations via immune and exhaustion mIF panels was performed and expression was normalized to total cell counts.

Results: Of the 25 patients analyzed, the median follow-up time was 23.9 months, during which 12 (48%) patients suffered a relapse with a median time to progression of 13.1 months. mIF revealed higher expression of HLA-DR (p = 0.019), CD8/LAG3 (p = 0.046), and CD8/CTLA4 (p = 0.027) among patients without relapse. Time to progression (TTP) and disease-specific survival (DSS) were stratified by median expression of each significant subpopulation and formally tested by the log-rank test. Higher than median expression of HLA-DR (p = 0.027), CD8/LAG3 (p = 0.039), and CD8/CTLA4 (p = 0.039) were significantly associated with TTP. Similarly, HLA-DR (p = 0.0069) and CD8/CTLA4 (p = 0.036) were significantly associated with improved DSS, whereas no significant observations were found with CD8/LAG3 (p = 0.11) expression. Stromal, but not tumoral expression of CD163 and CD163/PDL1 were significantly associated with improved TTP and DSS.

Conclusions: High expression of HLA-DR, CD8/CTLA4, and stromal expression of CD163 and CD163/PDL1 within pretreatment biopsy ESC samples was associated with significantly reduced rates of relapse. Increased presence of these markers suggests that an improved immune landscape is associated with less aggressive disease and may provide an opportunity for risk-based treatment strategies.