Background, rationale. Esophageal adenocarcinoma (EAC) has aggressive loco-regional spread with median overall survival ≤1 year. EAC patients undergo neoadjuvant chemotherapy or chemoradiotherapy (NAC/R) followed by surgery. Only about 20% of treated patients achieve a pathological complete response (pCR) with downstaging of tumor and/or lymph nodes (LNs), and significantly increased 5-year survival compared to nonresponders. However, there are no predictors of response to NAC/R directing the appropriate treatment selection for each patient. This prompts the definition of the mechanisms of response to NAC/R, to improve the stratification of patients and inform the design of more precise therapies that can increase the response rate.
Hypothesis. We hypothesise that pCR achieved in EAC patients upon NAC/R may result from pre-existing immunoreactive tumor microenvironment (TME) leading to stimulation of tumor-specific T cell responses, contributing to cancer elimination and long-term response, implying that NAC/R is an indirect immunotherapy approach.
Aims. Our preliminary results obtained on treatment-naïve EAC biopsies identified multidimensional signatures strongly supporting a pre-existing immunoreactive TME in the responders. We will confirm and extend the signatures predicting the response to NAC/R, by profiling new cohorts of treatment-naïve EAC biopsies.
Methods. We will integrate: 1. genomic signatures derived by WES and RNA-seq with 2. spatially resolved definition of their immune landscape and metabolic pathways by tissue transcriptomics, proteomics and metabolomics, and 3. correlate them with the regression of the tumor and LNs obtained after NAC/R.
Expected results and potential impact. We expect to define 1. immunological mechanisms of EAC response to NAC/R; 2. potential multivariable immune markers of response to NAC/R that better stratify patients; 3. new molecular pathways that may be harnessed to improve the therapeutic responses of EAC patients.