Cancerous tissue co-opts the immune system, suppressing its ability to destroy cancerous cells, and even gaining the assistance of immune cells in encouraging the growth of a tumor. There are many different mechanisms by which this happens, varied by immune cell type and form of cancer, comparatively few of which are well mapped and well understood. The active and well-funded cancer research community continues to explore the potential to interfere in these harmful interactions between cancer and immune system. The approach noted here is one of many, and typical of this sort of research program in that it targets a specific subset of immune cells.
Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning, and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells.
We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.