Highlights in Cancer Research: November 2022

Summary of the findings

For over a century, scientists and clinicians have appreciated that solid tumors typically spread to lymph nodes before metastasizing to other vital organs, yet the relevance of this nodal involvement has been unclear. While clinicians such as William Halsted suggested that the lymphatics serve as convenient conduit amenable to gradual dissemination throughout the host where the lymph nodes provide transiently hospitable microenvironments for the acquisition of additional metastatic traits, others have suggested that nodal involvement is a red herring, providing only diagnostic utility, but serving no functional role in subsequent metastasis. The latter stance has been informed more recently by sequencing approaches enabling phylogenetic reconstruction of metastatic clonal architecture, in some instances implicating distinct clonal origins of lymph node and distant metastases. In their recent manuscript, Reticker-Flynn, et al. discovered that lymph node colonization plays a critical step in metastasis not because the tumor cells therein are clonal precursors of distant metastases, but rather because such colonization promotes the generation of systemic tumor-specific immune tolerance that renders distant tissues amenable to metastatic seeding. They show that colonization of lymph nodes is aided by chronic exposure to interferons facilitating epigenetic reprogramming and the upregulation of molecules that confer resistance to Natural Killer (NK) cells and cytotoxic T cells. Once the tumors colonize the nodes, they induce differentiation of regulatory T cells (Tregs), an immunosuppressive subset of T cells, which bear T cell receptors (TCRs) that recognize tumor antigens. These Tregs play critical roles in the generation of systemic tumor-immune tolerance. These findings raise critical questions about the appropriate approach to management of patients with lymph node involvement. The authors suggest that while lymphadenectomy may aid in removal of tolerance-inducing metastases, it may also prevent the recognition of tumors by the immune system and inhibit the generation of anti-tumor immunity. Thus, future work on therapies that reverse tolerance and boost anti-tumor immunity following lymph node metastasis is needed, and the mechanisms that they have uncovered will serve as an informative blueprint for the development of such therapies.