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

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. 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. This article is highlighted in the In This Issue feature, p. 873

Identification of the immune subtype of ovarian cancer patients by integrated analyses of transcriptome and single-cell sequencing data

“…The function of T cells can be regulated by many immune microenvironment factors, such as M1 macrophage repolarization, B cell paracrine secretion and cross-talk among different T cell subsets 49 – 51 . Recently, relevant research results from chimeric antigen receptor macrophages (CAR-Ms) have shown that they can induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity 52 , 53 .…”

Discovering Immune-Mediated Mechanisms of Gastric Carcinogenesis Through Single-Cell RNA Sequencing

“…Taken together, these observations indicate that advancing gastric cancer microenvironments reduce IRF8 expression in CTLs and suppress antitumor immunity by promoting exhaustion. In patients treated with chemotherapy, there was an observed increase in expression of LAG3, an immune checkpoint molecule, within the tumor tissue of non-responders, suggesting chemotherapy may contribute to CTL exhaustion (33). Among responders to chemotherapy, however, there was an observed increase in NK cell, or possibly NKT cell, tumor infiltration.…”

“…While there may be more B cells recruited to diffuse tumors, there is still a consistent decrease in plasma cells as tumor grade and stage increase. Kim et al (2022) also found that after chemotherapeutic treatment, nonresponders have an observed increase in proportion of tumor infiltrating B cells, suggesting a tumor-associated cell type, not tumor cells directly, are responsible for triggering B cell apoptosis (33). Altogether, these data indicate that B cells are prevalent and capable of contributing to malignant transformation in early gastritis, but as the tumor develops, the TME promotes B cell apoptosis, thus limiting their contributions to tumor immunity.…”

“…In contrast, the M2-like macrophage fraction dominates in a less favorable classification (44). utilized previously published M1/M2 signature datasets to conclude that after chemotherapy there is an increase in M1like TAMs and a decrease in M2-like TAMs, suggesting chemotherapy improves the anti-tumor TAM phenotype in patients who respond to treatment (33). Yet Li et al (2022) used the increased expression of CD163 to define one TAM cluster as M2s and found that the gene signature of these cells was associated with regulating immune infiltration into the TME (24).…”

“…Among the published scRNAseq gastric cancer works, it is apparent that they have undertaken various approaches to their studies. Most groups obtained primary gastric cancer tissues from patients to generate scRNAseq data (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Some utilized previously published primary tumor datasets for further analysis (36)(37)(38)(39)(40)(41)(42)(43).…”