Open AccessEnhancing anticancer activity of checkpoint immunotherapy by targeting RAS
Author(s) -
Ward Antonio B.,
Keeton Adam B.,
Chen Xi,
Mattox Tyler E.,
Coley Alex B.,
Maxuitenko Yulia Y.,
Buchsbaum Donald J.,
Randall Troy D.,
Zhou Gang,
Piazza Gary A.
Publication year - 2020
Publication title -
medcomm
Language(s) - English
Resource type - Journals
ISSN - 2688-2663
DOI - 10.1002/mco2.10
Subject(s) - cancer research , immunotherapy , immune system , cancer immunotherapy , immune checkpoint , tumor microenvironment , biology , cancer cell , t cell , cancer , immunology , genetics
Approximately 30% of human cancers harbor a gain‐in‐function mutation in the RAS gene , resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS‐mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS‐driven oncogenesis also promotes immune evasion by increasing the expression of programmed cell death ligand‐1, reducing the expression of major histocompatibility complex molecules that present antigens to T‐lymphocytes and altering the expression of cytokines that promote the differentiation and accumulation of immune suppressive cell types such as myeloid‐derived suppressor cells, regulatory T‐cells, and cancer‐associated fibroblasts. Together, these changes lead to an immune suppressive tumor microenvironment that impedes T‐cell activation and infiltration and promotes the outgrowth and metastasis of tumor cells. As a result, despite the growing success of checkpoint immunotherapy, many patients with RAS‐driven tumors experience resistance to therapy and poor clinical outcomes. Therefore, RAS inhibitors in development have the potential to weaken cancer cell immune evasion and enhance the antitumor immune response to improve survival of patients with RAS‐driven cancers. This review highlights the potential of RAS inhibitors to enhance or broaden the anticancer activity of currently available checkpoint immunotherapy.