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2. Understanding the tumor immune microenvironment (TIME) for effective therapy

Author

Binnewies, Mikhail, Roberts, Edward W, Kersten, Kelly, Chan, Vincent, Fearon, Douglas F, Merad, Miriam, Coussens, Lisa M, Gabrilovich, Dmitry I, Ostrand-Rosenberg, Suzanne, Hedrick, Catherine C, Vonderheide, Robert H, Pittet, Mikael J, Jain, Rakesh K, Zou, Weiping, Howcroft, T Kevin, Woodhouse, Elisa C, Weinberg, Robert A, and Krummel, Matthew F

Subjects
Clinical Research, Vaccine Related, Immunization, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Inflammatory and immune system, Genotype, Humans, Immunotherapy, Neoplasm Metastasis, Neoplasms, Phenotype, Tumor Microenvironment, Medical and Health Sciences, Immunology
Abstract

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Published
2018

6. Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus

Author

Dorhoi, Anca, Kotze, Leigh A., Berzofsky, Jay A., Sui, Yongjun, Gabrilovich, Dmitry I., Garg, Ankita, Hafner, Richard, Khader, Shabaana A., Schaible, Ulrich E., Kaufmann, Stefan H.E., Walzl, Gerhard, Lutz, Manfred B., Mahon, Robert N., Ostrand-Rosenberg, Suzanne, Bishai, William, and Plessis, Nelita du

Subjects
AIDS vaccines -- Health aspects, AIDS (Disease) -- Health aspects, Vaccination -- Health aspects, Carboplatin -- Health aspects, Nilotinib -- Health aspects, Tuberculosis -- Health aspects, Antineoplastic agents -- Health aspects, Health care industry
Abstract

The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host- pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS., Innate suppressor cells in cancer, tuberculosis, and AIDS Immunosuppressive myeloid cells were originally described in tumor-bearing mice (1) and cancer patients (2) as pathologically activated or atypical myeloid cells. As [...]

Published
2020
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11. Supplementary Video 5 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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12. Supplementary Video 3 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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15. Data from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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17. Supplementary Video 6 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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18. Supplementary Video 4 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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20. Supplementary Figure 1 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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21. Supplementary Video 1 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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22. Supplementary Figure 3 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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23. Supplementary Figure 2 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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24. Supplementary Video 2 from IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development

Author

Smith, Courtney, primary, Chang, Mee Young, primary, Parker, Katherine H., primary, Beury, Daniel W., primary, DuHadaway, James B., primary, Flick, Hollie E., primary, Boulden, Janette, primary, Sutanto-Ward, Erika, primary, Soler, Alejandro Peralta, primary, Laury-Kleintop, Lisa D., primary, Mandik-Nayak, Laura, primary, Metz, Richard, primary, Ostrand-Rosenberg, Suzanne, primary, Prendergast, George C., primary, and Muller, Alexander J., primary

Published
2023
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41. The adaptor protein TRAF3 is an immune checkpoint that inhibits myeloid-derived suppressor cell expansion.

Author

Sining Zhu, Lalani, Almin I., Juan Jin, Sant'Angelo, Derek, Covey, Lori R., Kebin Liu, Young, Howard A., Ostrand-Rosenberg, Suzanne, and Ping Xie

Subjects
MYELOID-derived suppressor cells, IMMUNE checkpoint proteins, ADAPTOR proteins, KILLER cells, T cells
Abstract

Myeloid-derived suppressor cells (MDSCs) are aberrantly expanded in cancer patients and under other pathological conditions. These cells orchestrate the immunosuppressive and inflammatory network to facilitate cancer metastasis and mediate patient resistance to therapies, and thus are recognized as a prime therapeutic target of human cancers. Here we report the identification of the adaptor protein TRAF3 as a novel immune checkpoint that critically restrains MDSC expansion. We found that myeloid cell-specific Traf3-deficient (MTraf3-/-) mice exhibited MDSC hyperexpansion during chronic inflammation. Interestingly, MDSC hyperexpansion in M-Traf3-/- mice led to accelerated growth and metastasis of transplanted tumors associated with an altered phenotype of T cells and NK cells. Using mixed bone marrow chimeras, we demonstrated that TRAF3 inhibited MDSC expansion via both cell-intrinsic and cell-extrinsic mechanisms. Furthermore, we elucidated a GM-CSF-STAT3- TRAF3-PTP1B signaling axis in MDSCs and a novel TLR4-TRAF3-CCL22-CCR4-G-CSF axis acting in inflammatory macrophages and monocytes that coordinately control MDSC expansion during chronic inflammation. Taken together, our findings provide novel insights into the complex regulatory mechanisms of MDSC expansion and open up unique perspectives for the design of new therapeutic strategies that aim to target MDSCs in cancer patients. [ABSTRACT FROM AUTHOR]

Published
2023
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