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Peer-reviewedCC BY-NC 4.0Journal for ImmunoTherapy of Cancer

Spatial architecture of the tumor–stroma interface and transcriptional programs shape immunotherapy response in MSI-H gastrointestinal cancers

  • Xueshuai Han1
  • Kohei Yamashita2
  • Melissa Pool Pizzi2
  • Kyung Serk Cho1
  • Enyu Dai1
  • Yunhe Liu1
  • Kai Yu1
  • Yibo Dai1,3
  • Yang Liu1
  • Fuduan Peng1
  • Guangsheng Pei1
  • Tian Chu1
16 more authors
  • Matheus Sewastjanow-Silva2
  • Katsuhiro Yoshimura2
  • Yibo Fan2
  • Rebecca E Waters4
  • Qiong Gan4
  • Feng Yin4
  • Shilpa S Dhar2
  • Isadora Guimaraes Martins2
  • Jason Willis2
  • Mariela Blum Murphy2
  • Jenny J Li2
  • Brian D Badgwell5
  • Van K Morris2
  • Michael J Overman2
  • Linghua Wang1,3,6,7,8
  • Jaffer A Ajani2
8 affiliations
  1. 1Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  3. 3The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, Texas, USA
  4. 4Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  7. 7Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  8. 8Center for Integrated Cancer Architecture, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Abstract

Background Immune checkpoint blockade (ICB) therapy has demonstrated remarkable efficacy in microsatellite instability–high (MSI-H) gastrointestinal cancers, yet the determinants of sustained therapeutic response vs resistance remain poorly understood.Methods To comprehensively characterize the spatial architecture and transcriptional programs of tumors achieving sustained complete response (CR) versus those with non-sustained response (NR). We generated spatially resolved transcriptomic profiles from 18 tumor specimens obtained from 13 patients with gastrointestinal cancer, including 11 MSI-H and 2 microsatellite stable cases, with paired tissues collected before and after ICB therapy.Results Tumor cell meta-programs (MPs) exhibited distinct spatial gradients associated with response. The epithelial–mesenchymal transition MP was enriched at the invasive margin of pre- and post-NR tumors and diminished toward the core, while the cycling–high-interferon MP peaked at the periphery of pre-CR tumors. In pre-CR tumors, malignant cells co-localized with B cells and T follicular helper cells within tertiary lymphoid structures (TLSs), whereas in pre- and post-NR tumors, they were associated with macrophages and cancer-associated fibroblasts. Notably, TLSs in CR tumors exhibited stronger immune activation signatures irrespective of their maturation state. Cell–cell communication analysis further revealed immune activation at the tumor–stroma interface in CR tumors, contrasting with immunosuppressive signaling in NR tumors.Conclusions Our study reveals distinct spatial and transcriptional programs underlying differential responses to ICB in MSI-H gastrointestinal cancers, highlighting the pivotal role of tumor–immune–stromal organization and interaction in shaping therapeutic outcomes. These findings provide a framework for predicting response to better stratify patients and guiding future strategies to enhance immunotherapy efficacy.

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Cite

BibTeXRIS
BibTeX
@article{han2026spatial,
  title = {{Spatial architecture of the tumor–stroma interface and transcriptional programs shape immunotherapy response in MSI-H gastrointestinal cancers}},
  author = {Xueshuai Han and Kohei Yamashita and Melissa Pool Pizzi and Kyung Serk Cho and Enyu Dai and Yunhe Liu and Kai Yu and Yibo Dai and Yang Liu and Fuduan Peng and Guangsheng Pei and Tian Chu and Matheus Sewastjanow-Silva and Katsuhiro Yoshimura and Yibo Fan and Rebecca E Waters and Qiong Gan and Feng Yin and Shilpa S Dhar and Isadora Guimaraes Martins and Jason Willis and Mariela Blum Murphy and Jenny J Li and Brian D Badgwell and Van K Morris and Michael J Overman and Linghua Wang and Jaffer A Ajani},
  journal = {Journal for ImmunoTherapy of Cancer},
  year = {2026},
  month = oct,
  doi = {10.1136/jitc-2026-015653},
  url = {https://doi.org/10.1136/jitc-2026-015653},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Spatial architecture of the tumor–stroma interface and transcriptional programs shape immunotherapy response in MSI-H gastrointestinal cancers
AU  - Xueshuai Han
AU  - Kohei Yamashita
AU  - Melissa Pool Pizzi
AU  - Kyung Serk Cho
AU  - Enyu Dai
AU  - Yunhe Liu
AU  - Kai Yu
AU  - Yibo Dai
AU  - Yang Liu
AU  - Fuduan Peng
AU  - Guangsheng Pei
AU  - Tian Chu
AU  - Matheus Sewastjanow-Silva
AU  - Katsuhiro Yoshimura
AU  - Yibo Fan
AU  - Rebecca E Waters
AU  - Qiong Gan
AU  - Feng Yin
AU  - Shilpa S Dhar
AU  - Isadora Guimaraes Martins
AU  - Jason Willis
AU  - Mariela Blum Murphy
AU  - Jenny J Li
AU  - Brian D Badgwell
AU  - Van K Morris
AU  - Michael J Overman
AU  - Linghua Wang
AU  - Jaffer A Ajani
PY  - 2026
DA  - 2026/10/28
JO  - Journal for ImmunoTherapy of Cancer
DO  - 10.1136/jitc-2026-015653
UR  - https://doi.org/10.1136/jitc-2026-015653
AB  - Background Immune checkpoint blockade (ICB) therapy has demonstrated remarkable efficacy in microsatellite instability–high (MSI-H) gastrointestinal cancers, yet the determinants of sustained therapeutic response vs resistance remain poorly understood.Methods To comprehensively characterize the spatial architecture and transcriptional programs of tumors achieving sustained complete response (CR) versus those with non-sustained response (NR). We generated spatially resolved transcriptomic profiles from 18 tumor specimens obtained from 13 patients with gastrointestinal cancer, including 11 MSI-H and 2 microsatellite stable cases, with paired tissues collected before and after ICB therapy.Results Tumor cell meta-programs (MPs) exhibited distinct spatial gradients associated with response. The epithelial–mesenchymal transition MP was enriched at the invasive margin of pre- and post-NR tumors and diminished toward the core, while the cycling–high-interferon MP peaked at the periphery of pre-CR tumors. In pre-CR tumors, malignant cells co-localized with B cells and T follicular helper cells within tertiary lymphoid structures (TLSs), whereas in pre- and post-NR tumors, they were associated with macrophages and cancer-associated fibroblasts. Notably, TLSs in CR tumors exhibited stronger immune activation signatures irrespective of their maturation state. Cell–cell communication analysis further revealed immune activation at the tumor–stroma interface in CR tumors, contrasting with immunosuppressive signaling in NR tumors.Conclusions Our study reveals distinct spatial and transcriptional programs underlying differential responses to ICB in MSI-H gastrointestinal cancers, highlighting the pivotal role of tumor–immune–stromal organization and interaction in shaping therapeutic outcomes. These findings provide a framework for predicting response to better stratify patients and guiding future strategies to enhance immunotherapy efficacy.
SN  - 2051-1426
ER  -