Background Uncontrolled proliferation of metastatic solid tumors accounts for most cancer-related deaths. Metastatic tumors in the brain exemplify several key difficulties associated with researching and treating metastatic disease, including poor tissue penetration by anti-neoplastic drugs and tight control of infiltrating immune cell function. Potentiation of brain-infiltrating effector immune cells represents a favorable strategy for the clinical management of brain metastasis. Natural killer (NK) cells have shown particular promise in this regard.^{1 2} Accumulating clinical and pre-clinical evidence supports a vital role for NK cells in anti-metastatic immunity and has prompted the rapid development of both NK cell engagers and adoptive NK cell transplants—both of which have entered clinical trials.^2–11 Our work seeks to define NK cell anti-metastatic function in the brain with the goal of enhancing NK cell-mediated tumor control.

Methods Using cellular and molecular methods, we characterize the infiltration and function of NK cells and closely-related ILC1 cells in the brain metastatic microenvironment. We use flow cytometry to characterize tumor infiltration kinetics, antibody-mediated depletion and genetic knockout models to assess the individual contributions of NK cells and ILC1s, scRNA-seq to compare NK cell and ILC1 function and phenotype in the brain with that observed in peripheral tissues, and functional assays to identify strategies for NK cell potentiation in the brain.

Results We observe that NK cells rapidly infiltrate metastatic brain lesions but fail to robustly control metastatic outgrowth. scRNA-seq suggests functional deficits in brain-infiltrating NK cells relative to those infiltrating other organs. Cytokine supplementation suggests that NK cell deficits in the brain may be correctable. Our ongoing work seeks to explore effective strategies for NK cell enhancement in the response to brain metastasis.

Conclusions NK cells and closely-related ILC1s play crucial roles in the control of the metastatic spread of cancer. Our work describes the response of these cell types to metastatic colonization of the brain and suggests that NK cell functional deficiencies may be therapeutically targeted to improve metastatic control in the brain. This work maintains an end goal of rapid clinical translation of our findings in the adoptive NK cell therapy space.

References

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Ethics Approval The work described in this abstract was conducted with the approval of the UCI Institutional Animal Care and Use Committee and was performed under the supervision of the UCI University Laboratory Animal Resource.