MUC1-C promotes the suppressive immune microenvironment in non-small cell lung cancer

Bouillez, Audrey; Adeegbe, Dennis O.; Jin, Caining; Hu, Xiufeng; Tagde, Ashujit; Alam, Maroof; Rajabi, Hasan; Wong, Kwok‐Kin; Küfe, Donald

doi:10.1080/2162402x.2017.1338998

Cited by 47 publications

(49 citation statements)

References 25 publications

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“…However, in EBVaGC the immune milieu and the presence of viral antigens are associated with improved patient survival [51] as well as targets for immune therapies [53]. Other factors, such as the upregulation of COX-2 and MUC1 in gastric cancer cells, have been shown to influence the microenvironment by permitting immune evasion [54,55], vessel invasion, and metastatic spread [56]. By targeting the COX-2 and MUC1, there is a potential to improve cancer immunogenicity [54,55].…”

Section: Discussionmentioning

confidence: 99%

Molecular Classification of Gastric Cancer among Alaska Native People

Martinson

Mallari

Richter

et al. 2020

Cancers

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Gastric cancer is an aggressive and heterogeneous malignancy that often varies in presentation and disease among racial and ethnic groups. The Alaska Native (AN) people have the highest incidence and mortality rates of gastric cancer in North America. This study examines molecular markers in solid tumor samples from eighty-five AN gastric adenocarcinoma patients using next-generation sequencing, immunohistochemistry, and in situ hybridization analysis. AN patients have a low mutation burden with fewer somatic gene mutations in their tumors compared to other populations, with the most common mutation being TP53. Epstein-Barr virus (EBV) was associated with 20% of AN gastric cancers, which is higher than the world average of 10%. The inflammation marker, cyclooxygenase-2 (COX-2), is highly expressed in patients with the lowest survival rates. Mismatch repair deficiency was present in 10% of AN patients and was associated with patients who were female, 50 years or older, gene mutations, and tumors in the distal stomach. Program death-ligand 1 (PD-L1) was expressed in 14% of AN patients who were more likely to have MMR deficiency, EBV-associated gastric cancers, and mutations in the PIK3CA gene, all of which have been linked to clinical response to PD-1 inhibitors. These studies suggest a portion of AN gastric cancer patients could be candidates for immunotherapy. Overall, this study highlights future avenues of investigation for clinical and translational studies, so that we can improve early detection and develop more effective treatments for AN patients.

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Section: Discussionmentioning

confidence: 99%

Molecular Classification of Gastric Cancer among Alaska Native People

Martinson

Mallari

Richter

et al. 2020

Cancers

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“…Of further interest in this regard is the previously unrecognized role for MUC1-C in promoting immune evasion by driving PD-L1 expression and suppressing that of immune effectors, such as IFN-γ, in NSCLC cells (14). As a result, targeting MUC1-C function with the GO-203 inhibitor of the intracellular domain downregulates PD-L1, induces IFN-γ, and enhances effector activity of CD8 + tumor-infiltrating T cells in MUC1.Tg mouse models of NSCLC and TNBC (15,31) and in patients with acute myelogenous leukemia (32). These findings have highlighted the potential for targeting MUC1-Cexpressing cancer cells as an approach for reprogramming of the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate

et al. 2018

Self Cite

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Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly overexpressed on the surface of diverse human carcinomas and is an attractive target for the development of mAb-based therapeutics. However, attempts at targeting the shed MUC1 N-terminal subunit have been unsuccessful. We report here the generation of mAb 3D1 against the nonshed oncogenic MUC1 C-terminal (MUC1-C) subunit. We show that mAb 3D1 binds with low nM affinity to the MUC1-C extracellular domain at the restricted α3 helix. mAb 3D1 reactivity is selective for MUC1-C-expressing human cancer cell lines and primary cancer cells. Internalization of mAb 3D1 into cancer cells further supported the conjugation of mAb 3D1 to monomethyl auristatin E (MMAE). The mAb 3D1-MMAE antibody-drug conjugate (ADC) (a) kills MUC1-C-positive cells in vitro, (b) is nontoxic in MUC1-transgenic (MUC1.Tg) mice, and (c) is active against human HCC827 lung tumor xenografts. Humanized mAb (humAb) 3D1 conjugated to MMAE also exhibited antitumor activity in (a) MUC1.Tg mice harboring syngeneic MC-38/MUC1 tumors, (b) nude mice bearing human ZR-75-1 breast tumors, and (c) NCG mice engrafted with a patient-derived triple-negative breast cancer. These findings and the absence of associated toxicities support clinical development of humAb 3D1-MMAE ADCs as a therapeutic for the many cancers with MUC1-C overexpression.

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“…At present, the immunopathogenesis of NSCLC has not been fully elucidated (5). NSCLC cells escape from immune surveillance in vivo and induce a tumor immune suppressive microenvironment (6). The molecular mechanisms involved in the NSCLC-induced tumor immune suppressive microenvironment are still unknown (7).…”

Section: Introductionmentioning

confidence: 99%

Non-small Cell Lung Cancer Cells Modulate the Development of Human CD1c+ Conventional Dendritic Cell Subsets Mediated by CD103 and CD205

et al. 2019

Front. Immunol.

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Advanced non-small cell lung cancer (NSCLC) leads to a high death rate in patients and is a major threat to human health. NSCLC induces an immune suppressive microenvironment and escapes from immune surveillance in vivo. At present, the molecular mechanisms of NSCLC immunopathogenesis and the immune suppressive microenvironment induced by NSCLC have not been fully elucidated. Here, we focus on the effect of NSCLC cells on the development and differentiation of human CD1c + conventional dendritic cell (DC) subsets mediated by CD205 and CD103. The peripheral blood mononuclear cells (PBMCs) were isolated from NSCLC patients and healthy donors. DCs were induced and cocultured with primary NSCLC cells or tumor cell line H1299. DCs without incubation with tumor cells are control. The protein expression of costimulatory molecules such as CD80 and CD86, HLA-DR, pro-/anti-inflammatory cytokines such as IL-10 and IL-12, and CD205 and CD103 on CD1c + DCs was detected by flow cytometry. Our data revealed two new subpopulations of human CD1c + DCs (CD1c + CD205 + CD103 + and CD1c + CD205 + CD103 − DC) in healthy donors and NSCLC patients. NSCLC cells modulate the development of the CD1c + CD205 + CD103 + DC and CD1c + CD205 + CD103 − DC subpopulations in vitro and ex vivo. NSCLC cells also suppress the expression of signal molecules such as CD40, CD80, CD86, and HLA-DR on CD1c + DCs. In addition, the production of pro-inflammatory cytokines, including IL-12 and IL-23, is downregulated by NSCLC cells; however, the secretion of anti-inflammatory cytokines, such as IL-10 and IL-27, by CD1c + DCs is upregulated by NSCLC cells. Our results suggest that NSCLC cells may induce immune tolerogenic DCs, which block DC-mediated anti-tumor immunity in NSCLC patients. Our data may be helpful in revealing new cellular mechanisms related to the induction of tolerogenic CD1c + DCs by NSCLCs and the development of an immune suppressive microenvironment that causes tumor cells to escape immune surveillance. Our results indicate a potential role for CD1c + DC subsets mediated by CD205 and CD103 in DC-mediated immunotherapy to target NSCLC in the future.

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MUC1-C promotes the suppressive immune microenvironment in non-small cell lung cancer

Cited by 47 publications

References 25 publications

Molecular Classification of Gastric Cancer among Alaska Native People

Molecular Classification of Gastric Cancer among Alaska Native People

Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate

Non-small Cell Lung Cancer Cells Modulate the Development of Human CD1c+ Conventional Dendritic Cell Subsets Mediated by CD103 and CD205

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