Abstract
Chemotherapy is ubiquitous in first-line treatment of advanced gastric cancer, yet responses are heterogeneous, and little is known about mediators of chemotherapy response. To move forward, an understanding of the effects of standard chemotherapy on the tumor–immune microenvironment (TME) is needed. Coupling whole-exome sequencing, bulk RNA and single-cell transcriptomics from paired pretreatment and on-treatment samples in treatmentnaïve patients with HER2-positive and HER2-negative gastric cancer, we define features associated with response to platinum-based chemotherapy. Response was associated with on-treatment TME remodeling including natural killer (NK) cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Among chemotherapy nonresponders, we observed low/absent PD-L1 expression or modulation, on-treatment increases in WNT signaling, B-cell infiltration, and LAG3-expressing T cells coupled to an exodus of dendritic cells. We did not observe significant genomic changes in early on-treatment sampling. We provide a map of on-treatment TME modulation with standard chemotherapy and nominate candidate future approaches. SIGNIFICANCE: Using paired pretreatment and on-treatment samples during standard first-line chemotherapy, we identify chemotherapy-induced NK-cell infiltration, macrophage repolarization, and increased antigen presentation among responders. Increased LAG3 expression and decreased dendritic cell abundance were seen in nonresponders, emphasizing remodeling of the TME during chemotherapy response and resistance.
| Original language | English |
|---|---|
| Pages (from-to) | 984-1001 |
| Number of pages | 18 |
| Journal | Cancer Discovery |
| Volume | 12 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2022 Apr 1 |
Bibliographical note
Funding Information:This study was supported by AGA Research Foundation’s AGAGastric Cancer Foundation Ben Feinstein Memorial Research Scholar Award in Gastric Cancer (AGA2020-13-02, to S.J. Klempner), and the Stand Up to Cancer (SU2C) Gastric Cancer Interception Research Team Grant (grant number SU2C-AACR-DT-30-20) award (to H. Lee, S.J. Klempner, and J. Lee). This research grant is administered by the American Association for Cancer Research, the Scientific Partner of SU2C. This research was also supported by the SKKU Excellence in Research Award Research Fund, Sungkyunkwan University, 2020 (to J. Lee), and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and funded by the Ministry of Health & Welfare, Republic of Korea (grant number HR20C0025, to S.T. Kim and K.-M. Kim).
Funding Information:
A. Mehta reports personal fees from Third Rock Ventures, Asher Biotherapeutics, BioNTech, venBio Partners, Abata Therapeutics, and Checkmate Pharmaceuticals, and grants from Bristol Myers Squibb outside the submitted work. W.-Y. Park reports personal fees and other support from Geninus Inc. during the conduct of the study. S.J. Klempner reports personal fees from Merck, Bristol Myers Squibb, Astellas, Daiichi Sankyo, Pieris, Sanofi-Aventis, and Natera Oncology, and other support from Turning Point Therapeutics outside the submitted work. J. Lee reports grants from Stand Up To Cancer Gastric Cancer Interception Award, the Korea Health Technology R&D Project, and SKKU Excellence in Research Award Research Fund during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
This study was supported by AGA Research Foundation’s AGA-Gastric Cancer Foundation Ben Feinstein Memorial Research Scholar Award in Gastric Cancer (AGA2020-13-02, to S.J. Klempner), and the Stand Up to Cancer (SU2C) Gastric Cancer Interception Research Team Grant (grant number SU2C-AACR-DT-30-20) award (to H. Lee, S.J. Klempner, and J. Lee). This research grant is administered by the American Association for Cancer Research, the Scientific Partner of SU2C. This research was also supported by the SKKU Excellence in Research Award Research Fund, Sungkyunkwan University, 2020 (to J. Lee), and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and funded by the Ministry of Health & Welfare, Republic of Korea (grant number HR20C0025, to S.T. Kim and K.-M. Kim).
Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Oncology
