Scholarlink

Background <p>The success of novel antibody-drug conjugates, such as trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), has been pivotal in rendering “HER-2-low” gastric cancer (GC) a therapeutically targetable entity, expanding the population benefiting from anti-HER2 therapy by 2-3-fold. This advancement underscores the imperative to redefine and subclassify HER-2 status in GC. In this study, we innovatively proposed a four-tiered HER-2 classification standard for GC and, for the first time, conducted comparative analyses at the spatial single-cell multi-omics level across these four subgroups.</p> Methods <p>HER-2 status was recategorized into absent (immunohistochemistry (IHC) 0+, HER2_N), low (IHC 1+, HER2_L), moderate (IHC 2+/fluorescence in situ hybridization (FISH)-, HER2_M), and high (IHC 2+/FISH + or IHC 3+, HER2_H) groups. Primary tumor samples from 427 GC patients were collected and analyzed using Xenium5K in situ single-cell spatial transcriptomics (<i>n</i> = 153) and multiplex immunofluorescence (<i>n</i> = 427) detection base on tissue microassays.</p> Results <p>The proportion of samples that classified as HER2_N, HER2_L, HER2_M, and HER2_H was 43.13%, 22.88%, 11.11%, and 22.88%, respectively. Spatial HER-2 heterogeneous expression existed in 74.42% of HER-2 expressing GC and in 40.0% of HER2_H cases, which correlated with an unfavorable response to combined HER-2-targeted and immunotherapy and poor prognosis. In HER2_H group, lower infiltrates of exhausted T cells and regulatory T cells (Treg), higher cytotoxic activity of T cells, and enriched T cell-B cell niches were discovered, presenting a favorable tumor microenvironment that may benefit from immunotherapy. In HER2_M population, significantly higher CTLA4 + Treg infiltration, and their strengthened interactions with other cells via the CD80/CD86-CTLA4 axis were highlighted. HER2_L group exhibited increased infiltrates of SOX2-OT + mesenchymal cells and TGF-β-driven stromal-tumor cellular interactions. Moreover, HER2_N group presented a higher prevalence of diffuse and mixed histology, enriched endothelial cell-fibroblast-myeloid-derived suppressor cell niches, and augmented angiogenic activity.</p> Conclusion <p>Differences in clinicopathologic, molecular, and immunological underpinnings were underscored across GC with differential HER-2 expression status, providing a rationale for a novel quaternary HER-2 classification system and the development of stratified therapeutic strategies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Spatial single-cell multi-omics characterization of the tumor microenvironment heterogeneity by HER-2 expression status in gastric cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月10日

查看全文
  • Haoxin Peng,
  • Yang Chen,
  • Qian Yao,
  • Yueting Liang,
  • Xiaoyi Chong,
  • Yiming Luo,
  • Dan Liu,
  • Yakun Wang,
  • Yanyan Li,
  • Xujiao Feng,
  • Yu Sun,
  • Jifang Gong,
  • Zhi Peng,
  • Xiaotian Zhang,
  • Lin Shen

摘要

Background

The success of novel antibody-drug conjugates, such as trastuzumab deruxtecan (T-DXd) and disitamab vedotin (RC48), has been pivotal in rendering “HER-2-low” gastric cancer (GC) a therapeutically targetable entity, expanding the population benefiting from anti-HER2 therapy by 2-3-fold. This advancement underscores the imperative to redefine and subclassify HER-2 status in GC. In this study, we innovatively proposed a four-tiered HER-2 classification standard for GC and, for the first time, conducted comparative analyses at the spatial single-cell multi-omics level across these four subgroups.

Methods

HER-2 status was recategorized into absent (immunohistochemistry (IHC) 0+, HER2_N), low (IHC 1+, HER2_L), moderate (IHC 2+/fluorescence in situ hybridization (FISH)-, HER2_M), and high (IHC 2+/FISH + or IHC 3+, HER2_H) groups. Primary tumor samples from 427 GC patients were collected and analyzed using Xenium5K in situ single-cell spatial transcriptomics (n = 153) and multiplex immunofluorescence (n = 427) detection base on tissue microassays.

Results

The proportion of samples that classified as HER2_N, HER2_L, HER2_M, and HER2_H was 43.13%, 22.88%, 11.11%, and 22.88%, respectively. Spatial HER-2 heterogeneous expression existed in 74.42% of HER-2 expressing GC and in 40.0% of HER2_H cases, which correlated with an unfavorable response to combined HER-2-targeted and immunotherapy and poor prognosis. In HER2_H group, lower infiltrates of exhausted T cells and regulatory T cells (Treg), higher cytotoxic activity of T cells, and enriched T cell-B cell niches were discovered, presenting a favorable tumor microenvironment that may benefit from immunotherapy. In HER2_M population, significantly higher CTLA4 + Treg infiltration, and their strengthened interactions with other cells via the CD80/CD86-CTLA4 axis were highlighted. HER2_L group exhibited increased infiltrates of SOX2-OT + mesenchymal cells and TGF-β-driven stromal-tumor cellular interactions. Moreover, HER2_N group presented a higher prevalence of diffuse and mixed histology, enriched endothelial cell-fibroblast-myeloid-derived suppressor cell niches, and augmented angiogenic activity.

Conclusion

Differences in clinicopathologic, molecular, and immunological underpinnings were underscored across GC with differential HER-2 expression status, providing a rationale for a novel quaternary HER-2 classification system and the development of stratified therapeutic strategies.