{"id":2451,"date":"2019-01-07T17:03:41","date_gmt":"2019-01-07T08:03:41","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=2451"},"modified":"2019-01-07T17:03:41","modified_gmt":"2019-01-07T08:03:41","slug":"chemotherapy-and-tumor-immunity","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=2451","title":{"rendered":"Chemotherapy and tumor immunity"},"content":{"rendered":"

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A large increase in the incidence of cancers has been predicted for the coming years, with the number of cases worldwide rising from 15 million to 24 million between 2015 and 2035 (1<\/em><\/a>). The current revolution in cancer treatment\u2014cancer immunotherapy\u2014is based on the mobilization of the immune system to target cancer cells and is opening new avenues for achieving cancer control. However, evidence suggests that immunotherapies in many cancers are most effective when combined with other treatments, such as surgery, radiotherapy, and chemotherapy. On page 1416 of this issue, Ruscetti\u00a0et al.<\/em>\u00a0(2<\/em><\/a>) show that a combination of chemotherapy drugs inhibiting MEK (mitogen-activated protein kinase kinase) and CDKs (cyclin-dependent kinases) induces tumor cell senescence, a type of cell growth arrest, that alerts the innate immune system by activating natural killer (NK) cells, leading to immune control of the cancer.<\/p>\n

Therapies that enhance the development of an immune response against tumor cells are of high interest because the absence of antitumor immunity prior to treatment appears to be a major factor of resistance to immunotherapy. MEK and CDK inhibitors target the Ras-Raf-MEK-ERK (extracellular signal\u2013regulated kinase) pathway, which is a key pathway in many cancers. CDKs act downstream from ERK to control the cell cycle, and hence their activity can promote tumor cell division. BRAF inhibitors, such as dabrafenib, have potent antitumor activity, particularly when combined with MEK inhibitors, such as trametinib, in the treatment of melanoma and non\u2013small cell lung cancer (3<\/em><\/a>). The CDK4\/6 inhibitors abemaciclib, ribociclib, and palbociclib have been approved for use in breast cancer (4<\/em><\/a>). Ruscetti\u00a0et al.<\/em>\u00a0screened several chemotherapy agents and identified MEK and CDK4\/6 inhibitors as potent inducers of the senescent phenotype in the KP (Kras and p53) mouse model of lung adenocarcinoma.<\/p>\n

Cellular senescence is a programmed change in cell state associated with permanent growth inhibition (5<\/em><\/a>). It can be induced by stresses, such as DNA damage, shortening of telomeres (a biomarker of aging), oncogenic mutations, metabolic mitochondrial dysfunction, and inflammation. The senescence-associated secretory phenotype (SASP) is characterized by increased production of growth factors, proteases, and proinflammatory cytokines that recruit immune cells and stimulate them to clear the senescent cells. The precise mechanisms by which senescence is induced and the affected cells eliminated remain to be elucidated. Ruscetti\u00a0et al.<\/em>show that the treatment of tumor cells with MEK and CDK4\/6 inhibitors selectively triggers the antitumor functions of NK cells.<\/p>\n

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