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Supplementary Figure from Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

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posted on 2023-04-04, 00:02 authored by Ryul Kim, Minae An, Hyuk Lee, Arnav Mehta, You Jeong Heo, Kyoung-Mee Kim, Song-Yi Lee, Jeonghyeon Moon, Seung Tae Kim, Byung-Hoon Min, Tae Jun Kim, Sun Young Rha, Won Ki Kang, Woong-Yang Park, Samuel J. Klempner, Jeeyun Lee
Supplementary Figure from Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Funding

AGA Research Foundation's AGA-Gastric Cancer Foundation Ben Feinstein Memorial Research Scholar Award in Gastric Cancer

SU2C Gastric Cancer Interception Research Team Grant

Ministry of Health & Welfare, Republic of Korea

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ARTICLE 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 treatment-naïve 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. 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.This article is highlighted in the In This Issue feature, p. 873

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