Separable Cell Cycle Arrest and Immune Response Elicited through Pharmacological CDK4/6 and MEK Inhibition in RASmut Disease Models.

The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth.

Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression.

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis.

β-Catenin signaling in alveolar macrophages enhances lung metastasis through a TNF-dependent mechanism.

The main cause of malignancy-related mortality is metastasis. Although metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment, especially macrophages, which correlate with poor clinical outcomes. Macrophages consist of bone marrow-derived and tissue-resident populations.

Redirecting macrophage function to sustain their "defender" antitumor activity.

Macrophages are multi-functional innate immune cells that occupy normal or pathologic tissues, including cancer tissues. The importance of macrophage ontogeny and the transcriptional networks underlying their functional diversity are underappreciated in immuno-oncology. Here, we discuss the implications of these fundamental characteristics for therapeutically reprogramming macrophages to sustain their tumoricidal activities.

Inhibition of LSD1 in MDS progenitors restores differentiation of CD141 conventional dendritic cells.

The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141 conventional dendritic cells (CD141 cDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141 cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141 cDCs are associated with inferior overall survival in MDS patients.

Myeloid-driven mechanisms as barriers to antitumor CD8 T cell activity.

The adaptive immune system is essential for host defense against pathogenic challenges, and a major constituent is the CD8 cytotoxic T cell. Ordinarily, CD8 T cells are endowed with a unique ability to specifically recognize and destroy their targets. However, in cases where disease emerges, especially in cancer, the efficacy of the CD8 T cell response is frequently counterbalanced in a 'tug-of-war' by networks of tumor-driven mechanisms of immune suppression.