Characteristics of the Immune Cell Infiltration Landscape in Gastric Cancer to Assistant Immunotherapy

Abstract

Background: Gastric cancer (GC) was usually associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. It is urgent to screen reliable indices especially immunotherapy-associated parameters that can predict the therapeutic responses to immunotherapy of GC patients.Methods: Gene expression profile of 854 GC patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE84433) with their corresponding clinical and somatic mutation data. Based on immune cell infiltration (ICI) levels, molecular clustering classification was performed to identify subtypes and ICI scores in GC patients. After functional enrichment analysis of subtypes, we further explored the correlation between ICI scores and Tumor Mutation Burden (TMB) and the significance in clinical immunotherapy response.Results: Three subtypes were identified based on ICI scores with distinct immunological and prognostic characteristics. The ICI-cluster C, associated with better outcomes, was characterized by significantly higher stromal and immune scores, T lymphocytes infiltration and up-regulation of PD-L1. ICI scores were identified through using principal component analysis (PCA) and the low ICI scores were consistent with the increased TMB and the immune-activating signaling pathways. Contrarily, the high-ICI score cluster was involved in the immunosuppressive pathways, such as TGF-beta, MAPK and WNT signaling pathways, which might be responsible for poor prognosis of GC. External immunotherapy and chemotherapy cohorts validated the patients with lower ICI scores exhibited significant therapeutic responses and clinical benefits.Conclusion: This study elucidated that ICI score could sever as an effective prognostic and predictive indicator for immunotherapy in GC. These findings indicated that the systematic assessment of tumor ICI landscapes and identification of ICI scores have crucial clinical implications and facilitate tailoring optimal immunotherapeutic strategies.

Immune Profiling in Gastric Cancer Reveals the Dynamic Landscape of Immune Signature Underlying Tumor Progression

“…A number of previous studies have explored the immune microenvironment of gastric cancer through TCGA and GEO databases, showing a similar trend to our results, which validate our CyTOF data well (43,44). Other studies identified several prognosis-related genes and further constructed a prognostic model of gastric cancer patients based on public databases (45)(46)(47)(48)(49). Elucidating the detailed mechanism underlying the tumor-specific immune landscape of GC remains a future challenge to be tackled in the fields of tumor biology and immunology.…”

PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer

“… 61 Moreover, systematic reviews of gene expression profiles in patient biopsies revealed the importance of immune infiltration as an indicator for patient prognosis and a predictive factor for immunotherapy in gastric cancers. 62 , 63 Consistent with the aforementioned preclinical studies, the positive effects of oxaliplatin-based immunogenic (neoadjuvant) chemotherapy on the immune microenvironment has been confirmed by the meta-analysis of in silico data, as well as by multiplex immunostaining and next-generation sequencing (NGS) of gastric cancer biopsies, 64 altogether showing an elevated level of CTLs in the tumor immune infiltrate of patients treated with oxaliplatin, correlating with improved objective response rates. More direct proof for the synergistic effect of oxaliplatin and ICI therapy comes from the recent clinical trial CheckMate 649 65 targeting unresectable gastric and gastro-esophageal junction carcinomas.…”

Characterization of the immune cell function landscape in head and neck squamous carcinoma to assist in prognosis prediction and immunotherapy

“…Their findings revealed that patients with high TMB (TMB-H) exhibited a significantly higher response rate compared to those with low TMB (TMB-L). Several studies have also suggested a positive correlation between TMB-H and improved survival in gastric cancer and ovarian cancer [ 22 , 23 ]. However, in this study, it was observed that TMB-H was associated with poor survival in patients with HNSCC.…”