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). The current revolution in cancer treatment—cancer immunotherapy—is 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 et al. (2) 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.
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–regulated 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–small cell lung cancer (3). The CDK4/6 inhibitors abemaciclib, ribociclib, and palbociclib have been approved for use in breast cancer (4). Ruscetti et al. screened 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.
Cellular senescence is a programmed change in cell state associated with permanent growth inhibition (5). 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 et al.show that the treatment of tumor cells with MEK and CDK4/6 inhibitors selectively triggers the antitumor functions of NK cells.
Pharmacological inhibition of MEK and CDK4/6 induces retinoblastoma (RB) protein–mediated cellular senescence and SASP, leading to the activation of NK cells, which detect and eliminate senescent tumor cells. Several questions remain to be addressed, as indicated.
GRAPHIC: A. KITTERMAN/SCIENCE
NK cells are innate lymphoid cells (ILCs) with potent antitumor activities (6). The efficacy of some conventional anticancer agents, such as those used in chemotherapy, is not exclusively due to the direct killing of the tumor cells. Instead, some anticancer treatments can induce forms of cancer cell stress or death that alert the immune system, initiating an antitumor immune response (7). NK cells can be involved in these mechanisms. For instance, telomeric repeat–binding factor 2 (TRF-2) has been shown to induce a form of cellular stress that promotes the elimination of neoplastic cells in an NK cell–dependent manner (8). In addition, expression of ligands for NK cell–activating receptors, NKG2D and DNAM1, can be increased in cancer cells undergoing stress-induced senescent programs following treatment with chemotherapeutic agents, leading to NK cell activation (9). Senescent noncancer cells, such as decidual cells (10), fibroblasts (11), and hepatic stellate cells (12), can also trigger NK cell responses.
Given the dual potential of cellular senescence to halt the proliferation of tumor cells and recruit immune cells, interest in pro-senescence therapies for cancer treatment has been growing. However, several hurdles remain on the road to therapy-induced senescence as a means of treating cancer: optimization of the dose schedules and combinations required to induce cellular senescence and antitumor immunity, while overcoming the protumorigenic properties of senescent cells and the SASP. Indeed, the SASP has been described as a double-edged sword, because it can also induce tumor-promoting effects such as angiogenesis, epithelial-to-mesenchymal transition, and metastasis (13). It thus remains unclear whether it is preferable to induce senescence rather than cell death.
To date, attempts to make use of NK cells in cancer immunotherapy have focused on the initiation of a multilayered immune response culminating in protective and long-lasting antitumor immunity (6). Remarkably, Ruscetti et al. suggest that NK cells act as a natural senolytic, eliminating tumor cells rendered senescent by chemotherapy and controlling cancers without the assistance of other immune cell types. These findings raise important questions about the mechanisms by which senescent tumor cells are eliminated by NK cells and whether NK cells kill senescent tumor cells directly. Is the production of cytokines by NK cells, such as interferon-γ and GM-CSF (granulocyte-macrophage colony-stimulating factor), involved? Moreover, NK cells have many features in common with ILC1s (14). The selective involvement of NK cells in the control of KP tumors is striking, but its demonstration was based on the use of an NK1.1 monoclonal antibody that depletes both NK cells and ILC1s in mice. NK cells, ILC1s, and an intermediate subset (intILC1) can infiltrate mouse tumors and have opposing functions: NK cells favor tumor control, whereas intILC1s and ILC1s do not (15). Further dissection of the role of MEK and CDK4/6 inhibitors, and of other chemotherapy agents, in the composition and function of tumor-infiltrating ILCs is required. Does the recognition of senescent cells by NK cells initiate long-term protection against nonsenescent tumor cells? And most importantly, do these observations apply to human cancers?
Recent clinical results have supported the hypothesis that chemotherapy can boost immune responses and sensitize tumors to immunotherapies. However, we still know little about the underlying mechanisms, and more explorations are required to identify the most promising chemotherapy-immunotherapy combinations to further enhance clinical responses in cancer patients. The induction of senescence is one possible way in which chemotherapy and immunity may be able to join forces.
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