Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer

Li, Jianxia; Wu, Changbao; Hu, Huabin; Ge, Qi; Wu, Xueqian; Bai, Fan; Zhang, Jianwei; Cai, Yue; Huang, Yan; Wang, Chao; Yang, Jiaqi; Luan, Yizhao; Jiang, Zhongshan; Ling, Junqi; Wu, Zehua; Chen, Yaoxu; Xie, Zhi; Deng, Yao

doi:10.1016/j.ccell.2023.04.011

Cited by 94 publications

(40 citation statements)

References 87 publications

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“…In this study, patients with immune hot tumors were more likely to have reactive T cells, while other cancers, such as glioblastoma, had more hypofunctional T cells and were less likely to respond to ICI therapy alone [82]. Notably, several studies indicate there is continuous interaction between cancer cells and tumor stroma that may play an important role for the remodeling of the tumor microenvironment, which can impact antitumor immune response [83,84]. In a study of 19 patients with MSI-H CRC, single-cell RNA sequencing analysis showed that patients who achieved complete pathological response had more CD8+ T cells and CD20+ B cells in the tumor microenvironment, while those with persistent tumors had more CD4+ T regulatory cells [84].…”

Section: Discussionmentioning

confidence: 71%

“…Notably, several studies indicate there is continuous interaction between cancer cells and tumor stroma that may play an important role for the remodeling of the tumor microenvironment, which can impact antitumor immune response [83,84]. In a study of 19 patients with MSI-H CRC, single-cell RNA sequencing analysis showed that patients who achieved complete pathological response had more CD8+ T cells and CD20+ B cells in the tumor microenvironment, while those with persistent tumors had more CD4+ T regulatory cells [84]. Similar observations were noted for patients with MSI-H CRC and liver metastasis treated with ICI therapy [85].…”

Section: Discussionmentioning

confidence: 99%

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Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm

Özer

Vegivinti

Syed

et al. 2023

Cancers

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Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm

Özer

Vegivinti

Syed

et al. 2023

Cancers

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“…The therapeutic effect of conventional cytotoxic drugs, such as oxaliplatin, is closely related to the immune microenvironment [ 35 ]. GC is a cold tumor; therefore, understanding the changes in the immune microenvironment before and after NACT may accelerate the development of synergistic combination immunotherapy to improve the clinical effectiveness of immune checkpoint inhibitors [ 36 , 37 ]. According to the analysis based on the correlation between the score and PD‐L1, our model identified that the response group after NACT had a higher percentage of PD‐L1 positivity than the nonresponse group.…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis

Zhao,

Liu,

Ding

et al. 2024

The Journal of Pathology CR

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The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor‐infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre‐ and post‐NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan–Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long‐term survival in patients with advanced GC. Furthermore, tumor‐infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD‐L1)‐positive tumors was 31% (32/104) pre‐NACT and 49% (51/104) post‐NACT, and almost all patients with elevated PD‐L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.

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“…Lung cancer scRNA-seq data (GSE207422) [ 18 ] containing paired bulk RNA-seq data and colorectal cancer (CRC) scRNA-seq data GSE205506 [ 19 ] were downloaded from the Gene Expression Omnibus (GEO) ( https://www.ncbi.nlm.nih.gov/geo/ ) database for analysis. Breast cancer (BRCA) scRNA-seq data [ 20 ] were downloaded from lambrechtslab data access (vib.be) for external validation.…”

Section: Methodsmentioning

confidence: 99%

Integrated analysis of single-cell and bulk RNA sequencing data reveals a myeloid cell-related regulon predicting neoadjuvant immunotherapy response across cancers

Liu,

Sima,

Xiao

et al. 2024

J Transl Med

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Background Immunotherapy has brought about a paradigm shift in the treatment of cancer. However, the majority of patients exhibit resistance or become refractory to immunotherapy, and the underlying mechanisms remain to be explored. Methods Sing-cell RNA sequencing (scRNA‑seq) datasets derived from 1 pretreatment and 1 posttreatment achieving pathological complete response (pCR) patient with lung adenocarcinoma (LUAD) who received neoadjuvant immunotherapy were collected, and pySCENIC was used to find the gene regulatory network (GRN) between cell types and immune checkpoint inhibitor (ICI) response. A regulon predicting ICI response was identified and validated using large‑scale pan-cancer data, including a colorectal cancer scRNA‑seq dataset, a breast cancer scRNA‑seq dataset, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 5 ICI transcriptomic cohorts. Symphony reference mapping was performed to construct the myeloid cell map. Results Thirteen major cluster cell types were identified by comparing pretreatment and posttreatment patients, and the fraction of myeloid cells was higher in the posttreatment group (19.0% vs. 11.8%). A PPARG regulon (containing 23 target genes) was associated with ICI response, and its function was validated by a colorectal cancer scRNA‑seq dataset, a breast cancer scRNA‑seq dataset, TCGA pan-cancer cohort, and 5 ICI transcriptomic cohorts. Additionally, a myeloid cell map was developed, and cluster I, II, and III myeloid cells with high expression of PPARG were identified. Moreover, we constructed a website called PPARG (https://pparg.online/PPARG/ or http://43.134.20.130:3838/PPARG/), which provides a powerful discovery tool and resource value for researchers. Conclusions The PPARG regulon is a predictor of ICI response. The myeloid cell map enables the identification of PPARG subclusters in public scRNA-seq datasets and provides a powerful discovery tool and resource value.

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Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer

Cited by 94 publications

References 87 publications

Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm

Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm

Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis

Integrated analysis of single-cell and bulk RNA sequencing data reveals a myeloid cell-related regulon predicting neoadjuvant immunotherapy response across cancers

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