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Cancer Immunotherapy via Regulation of the Ubiquitin Proteasome Pathway
Author(s) -
Kumar Suresh,
Wu Jian,
LaRocque James,
Agarwal Saket,
Marblestone Jeffrey,
Kodrasov Matthew,
Weinstock Joseph,
Mattern Michael
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.897.33
Subject(s) - cancer immunotherapy , immunotherapy , immune system , ubiquitin ligase , cancer , cancer research , t cell , adoptive cell transfer , biology , ubiquitin , effector , proteasome , immune checkpoint , immunology , microbiology and biotechnology , gene , biochemistry , genetics
Immune evasion is a hallmark feature of tumors as they employ various strategies to suppress the immune system's ability to recognize and destroy cancer cells. Significant advances in the understanding of the mechanisms of cancer immune evasion have led to the successful development of immunotherapies that exhibit clinical efficacy against hematological as well as solid tumors. These include monoclonal antibodies, allogeneic hematopoietic stem cell transplantation, vaccination, cytokines, T cell checkpoint blockade, and adoptive transfer of engineered T cells. Due to the underlying complexity of cancer immune evasion, however, several different approaches will likely be necessary for effective therapeutic management. We are taking a dual targeting approach, focused on the ubiquitin proteasome pathway, to develop novel small molecule cancer immunotherapeutics. We have identified inhibitors of a deubiquitylase (DUB) that is highly expressed in regulatory T (Tregs) cells and plays a critical role in promoting Treg functions. In addition, we have identified inhibitors of an E3 ubiquitin ligase that negatively regulates T‐effector cell function. These inhibitors are expected to suppress Treg functions and promote T‐effector activities. A combination of such inhibitors should provide powerful anti‐cancer immunotherapy.