Loss of Fas Expression and Function Is Coupled with Colon Cancer Resistance to Immune Checkpoint Inhibitor Immunotherapy

Xiao, Wei; Ibrahim, Mohammed L.; Redd, Priscilla S.; Klement, John D.; Lu, Chunwan; Yang, Dafeng; Savage, Natasha M.; Liu, Kebin

doi:10.1158/1541-7786.mcr-18-0455

Cited by 32 publications

(38 citation statements)

References 47 publications

(78 reference statements)

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“…After T. gondii challenge, the expression of Gadd45 protein was up-regulated, while the expression of Fas protein was down-regulated, which affected p53 signaling pathway. Moreover, Fas protein plays an important role in suppressing colon cancer immune evasion (Xiao et al, 2018). Human surfactant protein D induces apoptosis in pancreatic cancer cell lines via Fas -mediated pathway (Kaur et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Sequencing Investigated the Tumor-Related Factors Changes After T. gondii Infection

et al. 2019

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Toxoplasma gondii is an intracellular parasite and causes a global epidemic parasitic disease. T. gondii-infection could inhibit the growth of tumor. In this study, the transcriptomes of samples were detected by deep sequencing analysis. The transcriptome data was compared with reference genome to perform sequence alignment and the further analysis. The analyses of differential expression and the differentially expressed genes were performed in the present study. Genes involved in P53 signaling pathway, COLORECTAL cancer pathway, NON-SMALL CELL LUNG cancer signaling pathway, and BREAST cancer signaling pathway were up-regulated or down-regulated among the samples. The KEGG analysis indicated that the cancer pathways changed after infection of T. gondii. Furthermore, tumor-related mRNAs from different samples had a large difference, which suggested that the difference might provide important information in resisting cancer. The protein results indicated that tumor-related protein changes occurred after infection of T. gondii. In conclusion, the infection changed the cancer pathways, which could possibly inhibit the growth of tumor.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Sequencing Investigated the Tumor-Related Factors Changes After T. gondii Infection

et al. 2019

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“…Cell apoptosis and death was evaluated using Allophycocyanin (APC)-conjugated annexin V/propidium iodide (PI) (BD PharMingen) staining followed by flow cytometry as previously described [17]. Chemotherapeutic agents, Cisplatin (Tocris Bioscience, Bristol, UK) or Gemcitabine (TCI America, Portland, OR, USA), were added into cultures and incubated for 48 to 72 h as indicated.…”

Section: Methodsmentioning

confidence: 99%

TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

Xiao

Wang

Howard

et al. 2019

Cancers

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Elevated tissue inhibitor of metalloproteinase-1 (TIMP-1) is a negative prognosticator in non-small cell lung carcinoma NSCLC patients. This study sought to identify mechanisms whereby TIMP-1 impacts anticancer therapy. Using NSCLC cells and their TIMP-1 knockdown clones, we examined the chemoresistance against two chemotherapeutic agents, Gemcitabine and Cisplatin, as identified by increased apoptosis in the knockdown clones. A bead-based cytokine screening assay identified interleukin-6 (IL-6) as a key factor in chemoresistance. Exogenous human recombinant rhTIMP-1 or rhIL-6 resulted in reduced apoptosis. IL-6 expression was closely correlated with TIMP-1 kinetics and was upregulated by the addition of exogenous TIMP-1 while TIMP-1 neutralizing antibodies delayed IL-6 elevation. IL-6 production was regulated by TIMP-1, exerting its effect via activation of downstream signal transducer and activator of transcription 3 (STAT3) signaling. Both molecules and their documented transcription factors were upregulated and activated in chemoresistant NSCLC cells, confirming the roles of TIMP-1 and IL-6 in chemoresistance. To examine the role of these genes in patients, survival data from lung adenocarcinoma (LUAD) patients was curated from the cancer genome atlas (TCGA) database. Kaplan-Meier analysis found that individuals expressing low TIMP-1 and IL-6 have a higher survival rate and that the two-gene signature was more significant than the single-gene status. We define for the first time, a regulatory relationship between TIMP-1 and IL-6 in NSCLCs, suggesting that the TIMP-1/IL6 axis may be a valuable prognostic biomarker. Therapeutic interventions directed at this dual target may improve overall prognosis while negatively affecting the development of chemoresistance in NSCLC.

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“…While it is possible to restore the tumor microenvironment and suppress tumor cell growth by blocking the PDL1-PD1 signaling pathway, it was found that this approach in MUC1-positive tumor-bearing mice promoted the infiltration of IFN-γ-producing CD8 + T-cells and inhibited the infiltration of myeloid cells, MDSCs and TAMs in the tumor microenvironment. This is pivotal to transform the tumor immunosuppressive microenvironment and enhance antitumor immune responses in favor of tumor eradication ( 41 ), since the presence of a high number of CD8 + T lymphocytes and fewer MDSCs and TAMs in tumor tissues is associated with improved prognosis ( 42 , 43 ). Interestingly, the present findings also suggest that targeting PDL1 in MUC1-positive tumor-bearing mice inhibited tumor growth and elicited a stronger antitumor effect than that in MUC1-negative tumor-bearing mice.…”

Section: Discussionmentioning

confidence: 99%

MUC1‑induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway

et al. 2020

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Mucin1 (MUC1) upregulation in colon cancer has been linked to poor patient outcomes and advanced stage at diagnosis. This is partially due to MUC1-mediated inhibition of T-cell proliferation affecting efficient lysis by cytotoxic lymphocytes, which contributes to escape from immune surveillance. In the present study, human colorectal cancer tissues were collected, and MUC1-positive and MUC1-negative colon cancer mouse models were prepared; subsequently, the number and function of immune cells in tumor tissues were measured using flow cytometry. The present study revealed that MUC1, as a tumor-associated antigen, can recruit more tumor-infiltrating lymphocytes into the tumor microenvironment compared with MUC1-negative colon cancer, but that these cells could not serve antitumor roles. Conversely, the present study demonstrated that MUC1-positive colon cancer attracted more regulatory T cells (Treg cells), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) to the tumor site than MUC1-negative colon cancer. Furthermore, the data suggested that programmed death protein 1 (PD1)-programmed death ligand 1 (PDL1) expression is greater in MUC1-positive colon cancer. Blocking the PD1-PDL1 signaling pathway reduced the percentage of Treg cells, MDSCs and TAMs in the tumor microenvironment, enhanced T-cell cytotoxicity and inhibited tumor growth, prolonging the survival time of MUC1-positive tumor-bearing mice. Therefore, the present study elucidated the role of MUC1 in tumor immune escape and provides a foundation for the application of PDL1 inhibitors to MUC1-positive colon cancer.

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Loss of Fas Expression and Function Is Coupled with Colon Cancer Resistance to Immune Checkpoint Inhibitor Immunotherapy

Cited by 32 publications

References 47 publications

Transcriptome Sequencing Investigated the Tumor-Related Factors Changes After T. gondii Infection

Transcriptome Sequencing Investigated the Tumor-Related Factors Changes After T. gondii Infection

TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC

MUC1‑induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway

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