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

Abstract

The profiling of the tumor immune microenvironment (TIME) is critical for guiding immunotherapy strategies. However, how the composition of the immune landscape affects the tumor progression of gastric cancer (GC) is ill-defined. Here, we used mass cytometry to perform simultaneous in-depth immune profiling of the tumor, adjacent tissues, and blood cells from GC patients and revealed a unique GC tumor-immune signature, where CD8+ T cells were present at a lower frequency in tumor tissues compared to adjacent tissues, whereas regulatory T cells and tumor-associated macrophages (TAMs) were significantly increased, indicating strong suppressive TIME in GC. Incorporated with oncogenic genomic traits, we found that the unique immunophenotype was interactively shaped by a specific GC gene signature across tumor progression. Earlier-stage GC lesions with IFN signaling enrichment harbored significantly altered T-cell compartments while advanced GC featured by metabolism signaling activation was accumulated by TAMs. Interestingly, PD-1 expression on CD8+ T cells was relatively higher in earlier-stage GC patients, indicating that these patients may derive more benefits from PD-1 inhibitors. The dynamic properties of diverse immune cell types revealed by our study provide new dimensions to the immune landscape of GC and facilitate the development of novel immunotherapy strategies for GC patients.

TAMs and PD-1 Networking in Gastric Cancer: A Review of the Literature

“…The flow diagram, illustrating the final selection process for eligible articles, is shown in Figure 2 . Seven studies investigated the correlation between the existence of TAMs and the expression of PD-L1 in GC cells [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ], and three studies explored the prognosis of patients with GC expressing high levels of PD-1+ TAMs [ 46 , 47 , 48 ]. Due to the significant heterogeneity of the sample across the scrutinized studies, it was not possible to perform a cumulative statistical analysis of pooled available evidence.…”

“…In Table 2 and Table 3 , the methods of analysis used for the expression of PD-L1 in GC specimens are presented for each article. Specifically, after the initial processing of the slides, they were incubated with a primary antibody, PD-L1, with an anti-human PD-L1 monoclonal antibody [ 3 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. In Ubukata et al’s.…”

“…Overall, it seems that PD-1+ TAMs have a pro-tumorigenic activity because they reduce the proliferation of CD8 T cells. On the other hand, PD-1+ TAMs do not correlate with the activity of CD4 T cells [ 47 , 48 ].…”

“…Furthermore, Wei et al observed that TAMs within the TME exhibited a high degree of PD-L1 expression. Additionally, more infiltration of macrophages was associated with poor prognosis [ 48 ]. Moreover, a strong correlation was identified between increased macrophage accumulation at the time of diagnosis and an unfavorable prognosis among patients with GC [ 46 , 47 , 48 ].…”

“…Additionally, more infiltration of macrophages was associated with poor prognosis [ 48 ]. Moreover, a strong correlation was identified between increased macrophage accumulation at the time of diagnosis and an unfavorable prognosis among patients with GC [ 46 , 47 , 48 ]. Specifically, a correlation was found between a higher accumulation of macrophages in tumors at the time of diagnosis and a poorer prognosis in GC patients.…”