Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Tripathi, Satyendra Chandra; Peters, Haley L.; Taguchi, Ayumu; Katayama, Hiroyuki; Wang, Hong; Momin, Amin A.; Jolly, Mohit Kumar; Çeliktaş, Müge; Rodriguez‐Canales, Jaime; Liu, Hui; Behrens, Carmen; Wistuba, Ignacio I.; Ben‐Jacob, Eshel; Levine, Herbert; Molldrem, Jeffrey J.; Hanash, Samir M.; Ostrin, Edwin J.

doi:10.1073/pnas.1521812113

Cited by 180 publications

(190 citation statements)

References 49 publications

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“…CTL specific for peptide/HLA-A2 complexes were generated as previously described (7,8,21). Briefly, T2 cells were loaded with peptide (30 μg) individually for 2 h in 10% RPMI, pooled, irradiated and washed four times to remove unbound peptide.…”

Section: Methodsmentioning

confidence: 99%

Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells

Peters

Tripathi

Kerros

et al. 2017

Cancer Immunology Research

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Immunotherapies targeting immune checkpoints have proven efficacious in reducing the burden of lung cancer in patients; however, the antigenic targets of these re-invigorated T cells remain poorly defined. Lung cancer tumors contain tumor-associated macrophages (TAM) and neutrophils, which release the serine proteases neutrophil elastase (NE) and proteinase 3 (P3) into the tumor microenvironment. NE and P3 shape the antitumor adaptive immune response in breast cancer and melanoma. In this report, we demonstrate that lung cancer cells cross-presented the tumor-associated antigen PR1, derived from NE and P3. Additionally, NE and P3 enhanced the expression of human leukocyte antigen (HLA) class I molecules on lung cancer cells and induced unique, endogenous peptides in the immunopeptidome, as detected with mass spectrometry sequencing. Lung cancer patient tissues with high intratumoral TAM were enriched for MHC class I genes and T-cell markers, and patients with high TAM and cytotoxic T lymphocyte (CTL) infiltration had improved overall survival. We confirmed the immunogenicity of unique, endogenous peptides with cytotoxicity assays against lung cancer cell lines, using CTL from healthy donors that had been expanded against select peptides. Finally, CTL specific for serine proteases–induced endogenous peptides were detected in lung cancer patients using peptide/HLA-A2 tetramers and were elevated in tumor-infiltrating lymphocytes. Thus, serine proteases in the tumor microenvironment of lung cancers promote the presentation of HLA class I immunogenic peptides that are expressed by lung cancer cells, thereby increasing the antigen repertoire that can be targeted in lung cancer.

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Section: Methodsmentioning

confidence: 99%

Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells

Peters

Tripathi

Kerros

et al. 2017

Cancer Immunology Research

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“…Lung cancer cells of mesenchymal phenotype show reduced expression of immunoproteosome subunits (PSMB8, PSMB9, PSMB10) specializing in processing peptides to be presented on the cell surface and express less than half of their proteins on HLA type I molecules than epithelial lung cancer cells do, which allows them a more successful evasion of the immune system [110] .…”

Section: Emt In Immune Escapementioning

confidence: 99%

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

Markiewicz

Żaczek²

2017

Pathobiology

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The metastatic spread of cancer accounts for the vast majority of cancer-related deaths. It is mediated by tumor cells circulating in blood (called circulating tumor cells, CTCs), which escaped from their established niches. CTCs give a unique opportunity to look into the metastatic cascade and to study the molecular processes supporting the spread of tumor cells throughout the body. As current therapies are not sufficiently effective in treating metastatic disease, it is important to determine cellular and molecular features of cancer cells that “seed” new tumors in distant organs at early stages. In this review we focus on the role of the epithelial-mesenchymal transition program in providing a survival advantage to metastasizing tumor cells, especially CTCs, and put it in the context of clinical findings.

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“…EGFR mutant tumors through activating the PD-1/L1 pathway and upregulating immunosuppressive cytokines, suppress T-cell function (39). This effect can be even stronger in tumors that have undergone epithelial to mesenchymal transition (EMT) and therefore lose the expression of the immunoproteasome, which generates peptides suitable for binding onto HLA I molecules and facilitates antigen presentation for CD8+ T-cell responses (43). STAT1 is a key positive regulator of immunoproteasome subunits whereas STAT3 activation, induced by oncogenic signals (44) or EMT, has an opposing role to STAT1 inhibiting its antitumor effects and immunosurveillance (43).…”

Section: Introductionmentioning

confidence: 99%

“…This effect can be even stronger in tumors that have undergone epithelial to mesenchymal transition (EMT) and therefore lose the expression of the immunoproteasome, which generates peptides suitable for binding onto HLA I molecules and facilitates antigen presentation for CD8+ T-cell responses (43). STAT1 is a key positive regulator of immunoproteasome subunits whereas STAT3 activation, induced by oncogenic signals (44) or EMT, has an opposing role to STAT1 inhibiting its antitumor effects and immunosurveillance (43). PD-L1 expression is significantly higher in ALK rearranged NSCLCs compared to NSCLCs with EGFR or KRAS mutation or to those with no genetic alteration of ALK, EGFR or KRAS (triple negative) (45,46).…”

Section: Introductionmentioning

confidence: 99%

The combination of checkpoint immunotherapy and targeted therapy in cancer

Karachaliou¹,

Cao²,

Sosa³

et al. 2017

Ann. Transl. Med.

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Abstract:The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC).

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Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome

Cited by 180 publications

References 49 publications

Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells

Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells

The Landscape of Circulating Tumor Cell Research in the Context of Epithelial-Mesenchymal Transition

The combination of checkpoint immunotherapy and targeted therapy in cancer

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