PhD student Univ. of Texas Southwestern Med. Ctr. Dallas, Texas, United States
Introduction/Rationale: Neutrophils can promote tumor progression by inhibiting the antitumor activity of natural killer (NK) cells known as the first line of defense against cancer. Studies in mice show that neutrophils can be polarized toward either an anti-tumor “N1” or a pro-tumor “N2” phenotype. However, it remains elusive how N1 and N2 neutrophil subtypes influence NK cell behaviors differently in human cancer. Here, we engineered a human cell-based microphysiological system to measure the distinct effect of N1 and N2 neutrophil subtypes on NK cell migration, motility, tumor cytotoxicity, and tumor infiltration.
Methods: We fabricated a three-channel microfluidic chip to examine preferential migration of NK-92MI cells toward LPS, IFN-γ, and IFN-β-polarized N1 and TGF-β-polarized N2 HL-60 neutrophils and NK-92MI cell cytotoxicity against PANC-1 tumor spheroids in the presence of N1 or N2 neutrophils. All cells were embedded in 3D collagen hydrogel to mimic the ECM of the tumor tissue and seeded into designated channels of the chip. Time-lapse imaging was performed to capture NK cell migration and tumor spheroid apoptosis over 24 h.
Results: NK-92MI cells showed preferential migration toward N1 over N2 neutrophils, although they showed lower motility in speed, displacement, and directionality after migration toward N1 than N2 neutrophils. N1 neutrophils restored NK-92MI cell cytotoxicity against pancreatic tumor spheroids while N2 neutrophils suppressed it, although both N1 and N2 neutrophils inhibited NK cell infiltration into tumor spheroids. N1 neutrophils also secreted a higher level of NK cell chemokine IP-10 and induced higher expressions of activation markers CD107a and IFN-γ by NK-92MI cells than N2 neutrophils.
Conclusion: This study reveals the dual role of human neutrophils in modulating NK cell behaviors and the complex crosstalk between different immune cell types, suggesting the reprogramming of neutrophils to reverse the immunosuppression on NK cells as a potential immunotherapy strategy for cancer.
