Immune and Stromal Cell Changes in Gastric Cancer

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Summary

Interpreting the reprogramming of the tumor microenvironment (TME) during the progression of gastric adenocarcinoma (GAC) offers the potential to disclose hitherto unknown therapeutic targets. In this study, comprehensive single-cell profiling of precancerous lesions, localized, and metastatic GACs was conducted, revealing modifications in TME cellular states and compositions throughout the course of GAC. The precancerous microenvironment is characterized by plentiful IgA+ plasma cells, with late-stage GACs dominated by immunosuppressive myeloid and stromal subsets. Six distinct TME ecotypes (EC1-6) were identified, with specific ecotypes associated with blood, uninvolved tissues, premalignant lesions, and metastases. Two unique ecotypes found in primary GACs correlate with specific histopathological and genomic features, as well as survival outcomes. The study observed an extensive remodeling of the stroma during GAC progression, with high SDC2 expression in cancer-associated fibroblasts (CAFs) correlating with aggressive tumor growth and adverse survival rates. This investigation provides an intricate GAC TME atlas, underlining potential targets for subsequent exploration.

Fig.1 Graphical abstract. (Wang, 2023)

Research Criteria

The pivotal concept of this scholarly investigation is to demystify the transformative shifts within the tumor microenvironment (TME) concurrent with the evolution of gastric adenocarcinoma (GAC) - a specific stomach cancer subtype. The authors employed single-cell RNA sequencing (scRNA-seq) to delve into the gene expression dynamics of various immune and stromal cell types inhabiting the TME, traversing the diverse stages of GAC from precancerous lesions to metastatic malignancies. The study sheds light on unique TME cell states and ecotypes, each demonstrating a correlation with the histopathologic, genomic, and clinical attributes of GAC.

Sample Type

Human PBMCs, GAC, and normal control samples.

Result—Landscapes of Single-Cell TMEs in Various Stages of GACs

Through rigorous analysis of single-cell RNA sequencing data from 68 samples collected from 43 patients, researchers have illuminated the complex cellular landscapes constituting the tumor microenvironment (TME) at various stages of gastric adenocarcinoma (GAC). The study identified ten distinct cell lineages, segmented into three major compartments: lymphoid (77%), myeloid (13%), and stromal cells (10%). This comprehensive exploration revealed dramatic shifts in cellular composition during disease progression, with plasma and mast cell proportions escalating in precancerous stages before sharply declining in primary GACs and being largely absent in metastases. Conversely, myeloid and CD4+ T cells showed a distinct increase from premalignant lesions to primary GACs, persisting at high levels in metastases. Further, the study correlated TME cell characteristics with key clinical and histopathological features, thus providing invaluable insights into GAC's complex cellular dynamics.

Fig.2 Immune and stromal cell landscapes in GACs at different stages. (Wang, 2023)

Result—Changes in T cell States Occur as GAC Progresses, with Immunosuppressive Myeloid Subsets Dominating in Tumors at Advanced Stages

The meticulous examination of T and natural killer (NK) cell subsets in the progression of gastric adenocarcinomas (GACs) has divulged seven principal varieties, including CD4+ and CD8+ T cells, NK, double-negative T, gamma delta T, NKT, and proliferating cells. Moreover, seven CD4+ T cell states and ten CD8+ T cell states were discerned, with certain subpopulations more prevalent in tissue samples. Notably, the regulatory T cells were particularly enriched in primary GACs. The study also mapped a differentiation trajectory for CD8+ T cells, highlighting the heterogeneity of their states and diverse differentiation paths likely shaped by local contexts. In addition, the investigation revealed a growing prevalence of immunosuppressive myeloid subsets in advanced-stage tumors, demonstrating a stark transition from immune-stimulating to immunosuppressive states, further underlining the complex interplay of immune cell subsets in the tumor microenvironment during GAC evolution.

Fig.3 Characterization of T-cell states. (Wang, 2023)

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Reference

1. Wang, R.; et al. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression. Cancer Cell. 2023, S1535-6108(23): 00215-5.