Regional activation of myosin II in cancer cells drives tumor progression via a secretory cross-talk with the immune microenvironment
Tumor cells at the invasive front of primary melanomas differ from the cells elsewhere in the tumor. These amoeboid cells are rounded, enriched in phosphorylated myosin chains (indicative of high myosin II activity), and key to metastasis. Amoeboid cells secrete factors that attract monocytes and promote their differentiation into protumor macrophages. Blocking myosin II activity prevents the surrounding macrophages from supporting tumor growth. IL1α from the macrophages induces NF-κB activation in the amoeboid cells, completing a protumor loop.
Clonal deletion of tumor-specific T cells by interferon-γ confers therapeutic resistance to combination immune checkpoint blockade
One can have too much of a good thing. Although combining anti–CTLA-4 with anti–PD-1 can induce effective antitumor immunity when tumor burdens are high, when they are low, this combination increases the susceptibility of tumor-specific T cells to apoptosis. T cells in the low-tumor state are less exhausted and produce increased amounts of IFNγ but also bare more IFNγ receptors, leading to depletion of higher-frequency clones and loss of memory responses. Thus, finding the sweet spot for combination therapy may be necessary to avoid inducing immune-intrinsic resistance to treatment.
Anti-tumor immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells
Cross-presentation by dendritic cells is limited by the protein YTHDF1. The binding of YTHDF1 to the 3'UTR of mRNAs that are modified with N6-adenosine methylation increases the translation of cathepsins, causing rapid degradation of endocytosed antigens. YTHDF1-deficient dendritic cells (DCs) have enhanced cross-presentation. Mice whose DCs lack YTHDF1 reject tumors more readily and respond better to checkpoint inhibitors. Thus, cross-presentation is key for antitumor immunity, and modulation of cross-presentation through YTHDF1 provides another target for cancer immunotherapy in combination with checkpoint inhibitors.
Neutrophils escort circulating tumor cells to enable cell cycle progression
In breast cancer patients, some circulating tumor cells (CTCs) cluster with neutrophils. These CTC-neutrophil clusters are more proliferative, metastatic, and correlate with lower progression-free and overall survival than CTCs alone in mouse models. Although mutational burdens are similar to CTCs alone, the CTC-neutrophil clusters have recurrent mutations in TLE1 and MERTK, which promote myeloid infiltration into tumors. VCAM1 is required for CTC interaction with neutrophils, and blocking this prevents cluster formation, providing a potential therapeutic target to reduce metastasis.
Ribosomal proteins regulate MHC class I peptide generation for immunosurveillance
Ribosomes contain 80 proteins involved in translation. Wei et al. deleted each one to ascertain their influence on the peptides presented by MHC class I. Two large ribosomal subunit proteins, RPL28 and RPL6, have opposite effects on presentation of viral peptides if missing (increased and decreased, respectively), and depletion of the small subunit protein RPS28 increased the presentation of host peptides. Thus, tumors can manipulate the antitumor response of T cells through their altered ribosomal composition and mutated ribosomal proteins, both of which affect the peptides presented to T cells.
Commensal microbiota promote lung cancer development via γδ T cells
Effects of the lung's microbiome on tumors was studied in a mutant-Kras/p53– mouse model. Commensal microbiota promote inflammation and cancer progression through resident γδ T cells. The microbes are required for γδ T-cell expansion and activation, subsequent neutrophil infiltration, and development of lung adenocarcinomas. Disruption of the microbiota-mediated activation of γδ T cells may aid inactivating this route to lung cancer.
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