Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment

Liu, Qiaofei; Wu, Huanwen; Li, Yuan; Zhang, Ronghua; Kleeff, Jörg; Zhang, Xiang; Cui, Ming; Liu, Jing-Kai; Li, Tong; Gao, Jinyang; Pan, Boju; Wu, Wenming; Wang, Weibin; Zhou, Li; Guo, Junchao; Dai, Menghua; Zhang, Taiping; Liao, Quan; Lü, Zhaohui; Zhao, Yupei

doi:10.1007/s00262-020-02542-7

Cited by 45 publications

(41 citation statements)

References 44 publications

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“…JS-987). Totally, 97 pairs of tumor and para-tumor normal samples of patients diagnosed with PDAC were collected as the description of our previous study [17]. All of the cases were pathologically confirmed to be PDAC, and R0 radical resection was achieved and at least three cycles of adjuvant chemotherapy were performed for each patient.…”

Section: Patient Cohortmentioning

confidence: 99%

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Liu

Zhang

et al. 2021

Cancer Cell Int

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Background Emerging evidence has shown that intra-tumor immune features are associated with response to immune checkpoint blockade (ICB) therapy. Accordingly, patient stratification is needed for identifying target patients and designing strategies to improve the efficacy of ICB therapy. We aimed to depict the specific immune features of patients with pancreatic cancer and explore the implication of immune diversity in prognostic prediction and individualized immunotherapy. Methods From transcriptional profiles of 383 tumor samples in TCGA, ICGC, and GEO database, robust immune subtypes which had different response immunotherapy, including ICB therapy, were identified by consensus clustering with five gene modules. DEGs analysis and tumor microarray were used to screen and demonstrate potential targets for improving ICB therapy. Results Three subtypes of pancreatic cancer, namely cluster 1–3 (C1–C3), characterized with distinct immune features and prognosis, were generated. Of that, subtype C1 was an immune-cold type in lack of immune regulators, subtype C2, with an immunosuppression-dominated phenotype characterized by robust TGFβ signaling and stromal reaction, showed the worst prognosis, subtype C3 was an immune-hot type, with massive immune cell infiltration and in abundance of immune regulators. The disparity of immune features uncovered the discrepant applicability of anti-PD-1/PD-L1 therapy and potential sensitivity to other alternative immunotherapy for each subtype. Patients in C3 were more suitable for anti-PD-1/PD-L1 therapy, while patients in the other two clusters may need combined strategies targeted on other immune checkpoints or oncogenic pathways. A promising target for improving anti-PD-1/PD-L1 treatment, TGM2, was screened out and its role in the regulation of PD-L1 was investigated for the first time. Conclusion Collectively, immune features of pancreatic cancer contribute to distinct immunosuppressive mechanisms that are responsible for individualized immunotherapy. Despite pancreatic cancer being considered as a poor immunogenic cancer type, the derived immune subtypes may have implications in tailored designing of immunotherapy for the patients. TGM2 has potential synergistic roles with ICB therapy.

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Section: Patient Cohortmentioning

confidence: 99%

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Liu

Zhang

et al. 2021

Cancer Cell Int

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“…Second, adjuvant treatment modality including chemotherapy and radiotherapy could affect TAMCs [206][207][208][209][210], or TAMCs itself could elicit resistance to adjuvant therapies [211]. Furthermore, TAMC-targeting agents influence responses to chemotherapy and radiotherapy [212][213][214]; these secondary effects should be considered when adjuvant therapies and TAMC-targeting agents are concurrently applied. Lastly, TAMCs have variable physiological functions other than immunological functions, resulting in side effects of TAM-targeting agents.…”

Section: Discussionmentioning

confidence: 99%

Role of Tumor-Associated Myeloid Cells in Breast Cancer

Jin

Koo

2020

Cells

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Stromal immune cells constitute the tumor microenvironment. These immune cell subsets include myeloid cells, the so-called tumor-associated myeloid cells (TAMCs), which are of two types: tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Breast tumors, particularly those in human epidermal growth factor receptor 2 (HER-2)-positive breast cancer and triple-negative breast cancer, are solid tumors containing immune cell stroma. TAMCs drive breast cancer progression via immune mediated, nonimmune-mediated, and metabolic interactions, thus serving as a potential therapeutic target for breast cancer. TAMC-associated breast cancer treatment approaches potentially involve the inhibition of TAM recruitment, modulation of TAM polarization/differentiation, reduction of TAM products, elimination of MDSCs, and reduction of MDSC products. Furthermore, TAMCs can enhance or restore immune responses during cancer immunotherapy. This review describes the role of TAMs and MDSCs in breast cancer and elucidates the clinical implications of TAMs and MDSCs as potential targets for breast cancer treatment.

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“…Interestingly, TGFβ-mediated EMT induces N-glycosylation of CD147/basigin by N-acetylglucosaminyltransferase V (GnT-V) that enhances interactions with integrinβ1 and promotes HCC metastasis [96]. Furthermore, TGFβ1 and GM-CSF suppress chemotherapeutic effects by modulating the tumor microenvironment in pancreatic cancer [97]. These findings suggest that both secreted protein and protein-protein interactions on the cell surface are critical for tumor progression.…”

Section: Growth Factorsmentioning

confidence: 99%

Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

Huang

Chang

Wang

et al. 2021

Cells

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Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.

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Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment

Cited by 45 publications

References 44 publications

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Role of Tumor-Associated Myeloid Cells in Breast Cancer

Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

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