Cancer progression and the invisible phase of metastatic colonization

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment.

The ability of the immune system to eliminate and shape the immunogenicity of tumors defines the process of cancer immunoediting 1 . Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumors and have resulted in durable responses in cancer patients that did not respond to previous treatments. However, only a subset of patients benefit from immunotherapy and more knowledge about what is required for successful treatment is needed 2–4 . While the role of tumor neoantigen-specific CD8+ T cells in tumor rejection is well established 5–9 , the roles played by other T cell subsets have received less attention. Here we show spontaneous and immunotherapy-induced anti-tumor responses require the activity of both tumor antigen specific CD8+ and CD4+ T cells, even in tumors that do not express MHC class II. Additionally, tumor cell expression of MHC class II-restricted antigens is required at the site of successful rejection, indicating that CD4+ T cell activation must also occur in the tumor microenvironment. These findings suggest that MHC class II-restricted neoantigens have a key function in the anti-tumor response that is nonoverlapping with that of MHC class I-restricted neoantigens and therefore need to be considered when identifying patients who will most benefit from immunotherapy.

Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.