Immune Infiltration in Gastric Cancer Microenvironment and Its Clinical Significance

Abstract

Immunotherapy has developed rapidly and has gradually become one of the important methods for treatment of gastric cancer (GC). The research on tumor infiltrating immune cells (TIICs) and immune-related genes in the tumor microenvironment (TME) greatly encourages the development of immunotherapy. The devolution algorithm (CIBERSORT) was applied to infer the proportion of 22 TIICs based on gene expression profiles of GC tissues, which were downloaded from TCGA and GEO. TCGA was utilized to analyze the differential expression of immune-related genes, and explore the potential molecular functions of these genes. We have observed the enrichment of multiple TIICs in microenvironment of GC. Some of these cells were closely related to tumor mutational burden (TMB), microsatellite instability (MSI), Fuhrman grade, and TNM staging. Survival analysis showed that the infiltration level of CD8+ T cells, activated CD4+ memory T cells and M2 macrophages were significantly related to the prognosis of GC patients. The functional enrichment analysis of immune-related genes revealed that these genes were mainly associated with cytokine activation and response. Four significant modules were screened by PPI network and 20 key genes were screened from the modules. The expression levels of CALCR and PTH1R are strikingly related to the expression of immune checkpoint and the prognosis of GC patients. The type and number of TIICs in microenvironment of GC, as well as immune-related genes are closely related to tumor progression, and can be used as important indicators for patient prognosis assessment.

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

“…Tumors with enriched TAMs infiltrate would represent advanced stages of GC in full progression and be virtually resistant to the host's immune system. 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).…”

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.…”

Relationship of FDG PET/CT Textural Features with the Tumor Microenvironment and Recurrence Risks in Patients with Advanced Gastric Cancers

“…Macrophages in the tumor microenvironment predominantly exhibit an M2 phenotype with high CD163 expression [ 36 , 37 ]. M2 macrophages play a crucial role in promoting gastric cancer progression and metastasis and suppressing immune reactions in the tumor microenvironment, revealing a poor prognosis in tumors with increased M2 macrophage infiltration [ 10 , 37 ]. CD8 T lymphocytes are considered to perform important functions in anti-tumor reactions, and several studies have shown an improved prognosis in gastric cancers with a high density of CD8 T lymphocytes [ 10 , 38 ].…”

“…M2 macrophages play a crucial role in promoting gastric cancer progression and metastasis and suppressing immune reactions in the tumor microenvironment, revealing a poor prognosis in tumors with increased M2 macrophage infiltration [ 10 , 37 ]. CD8 T lymphocytes are considered to perform important functions in anti-tumor reactions, and several studies have shown an improved prognosis in gastric cancers with a high density of CD8 T lymphocytes [ 10 , 38 ]. In contrast, other studies revealed contradictory results, showing worse survival in patients with high intra-tumoral CD8 T lymphocyte density, and suggested that the effects of CD8 T lymphocytes on cancer cells are dependent on the histopathological features of cancer cells and other immune factors in the tumor microenvironment, such as programmed death-ligand 1 (PD-L1) expression [ 35 , 38 , 39 ].…”

“…Furthermore, several recent studies have found that interactions between gastric cancer cells and their microenvironment play a key role in cancer progression and metastasis [ 9 ]. In previous studies investigating the tumor microenvironment, along with immune cells, including T lymphocytes and macrophages, cytokines and proteins involved in the inflammatory response of the microenvironment, such as interleukin-6 (IL-6) and matrix metalloproteinase-11 (MMP-11), showed significant prognostic values in predicting clinical outcomes in patients with gastric cancer [ 10 , 11 , 12 ].…”