170P - Digital spatial profiling to uncover biomarkers for response prediction in locally advanced gastric cancer patients treated with neoadjuvant chemotherapy

Background

The interaction between gastric cancer (GC) tumor cells and tumor microenvironment could impact on the response to conventional chemotherapies (CT). The aim of this study was to obtain a wide transcriptomic profile with spatial resolution of tissue samples from locally advanced GC patients (pts) who present extremely different response to neoadjuvant CT (NCT).

Methods

Nanostring GeoMx Digital Spatial Profiler (DSP) was performed on pre-therapy biopsies and matched surgical specimens from 6 patients who received NCT. Three pts reached a complete pathological response (CRs), the remaining do not respond (NRs). Regions of interest were visualized on FFPE sections based on immunofluorescent staining for nuclear (DNASyto13), tumor (Pan-cytokeratin) and immune cell (CD45) compartments. Expression levels of more 1,800 genes were evaluated by using the Cancer Transcriptome Atlas (CTA) panel. Transcripts counts were generated using NextSeq 550 instrument (Illumina) and analysed by DSP analysis suite (Nanostring). Effector memory T cells were analysed by immunoistochemistry using CD45RO antibody.

Results

Cells in the tumor compartment of CRs presented an enrichment of deregulated pathways involved in extracellular matrix (ECM) organization and degradation, whereas key pathways involved in cell junction organization, interferon signaling and cell-cell communication were upregulated in NRs. Higher levels of intratumoral CD45RO staining was observed in CRs. A high number of pathways, mainly related to the ECM remodelling and cell surface interaction, as for tumoral cells, resulted upregulated in immune compartment of CRs. Conversely, lymphocytes in NRs were characterized by enrichment in genes involved in the signaling by B cell receptor and generation of second messenger molecules.

Conclusions

A comprehensive characterization of the expression profile of tumor and immune cells showed the contribution of both compartments in the chemosensitivity, mainly through the regulation of ECM organization and remodeling. DSP-based analyses will help to decipher the different responses of GC patients to chemotherapy, enabling the identification of potential biomarker signatures.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \"Dino Amadori\".

Funding

Italian Ministry of Health within the ERAPerMed Project GRAMMY (ERP-2019-23671108; GRAMMY, 2019-275).

Disclosure

All authors have declared no conflicts of interest.