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Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

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Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Thoracic/Head-Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
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Departments of Melanoma Medical Oncology–Research and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Integrative Biology and Pharmacology, The University of Texas Health Sciences Center, Houston, TX 77030, USA
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Department of Pathology (Anatomical), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(5), 714; https://doi.org/10.3390/cancers11050714
Received: 26 February 2019 / Revised: 14 May 2019 / Accepted: 20 May 2019 / Published: 24 May 2019
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors. View Full-Text
Keywords: CD8 T Cells; immune blockade; NSCLC; reversal of EMT; tumor microenvironment; tumor plasticity; TNBC CD8 T Cells; immune blockade; NSCLC; reversal of EMT; tumor microenvironment; tumor plasticity; TNBC
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Soundararajan, R.; Fradette, J.J.; Konen, J.M.; Moulder, S.; Zhang, X.; Gibbons, D.L.; Varadarajan, N.; Wistuba, I.I.; Tripathy, D.; Bernatchez, C.; Byers, L.A.; Chang, J.T.; Contreras, A.; Lim, B.; Parra, E.R.; Roarty, E.B.; Wang, J.; Yang, F.; Barton, M.; Rosen, J.M.; Mani, S.A. Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy. Cancers 2019, 11, 714.

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