Natural Killer cells secreting interferon gamma and wnt ligands promote tumor progression in triple negative breast cancer

Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer, with limited therapeutic options and high mortality. While the high level of immune infiltrate in TNBCs suggested that they would be amenable to targeted immunotherapy, phase-I clinical trials with PDL-1 inhibitors have shown very limited responses. Thus, additional understanding of the immune landscape in the TME of TNBC patients is representing a clinically unmet need. Natural Killer (NK) cells are cytotoxic lymphocytes, classically known to act against tumor cells. However, preliminary studies with our new aggressive and metastatic TNBC mouse model with increased PD-L1, a downstream target of IFN-gamma signaling showed that NK cells that are source of IFN-gamma were surprisingly overrepresented in aggressive TNBCs. We have observed distinct subsets of NK cells in aggressive TNBCs through scRNA seq that express IFN-gamma and low levels of cytotoxic granzymes. Both, in silico analysis and high CD56 expression in patient tumor tissues revealed that increased number of CD56bright NK cells are significantly correlated with poor Overall Survival (OS) in TNBC patients. Pharmacological blocking of NK cells either alone or in combination with PD-L1 in tumor bearing mice reduced tumor burden and metastasis. Functional studies further demonstrated that tumor NK cells from aggressive TNBC are less cytotoxic and were pro-tumorigenic. This work unravels the paradoxical function and identity of pro-tumorigenic NK cell subsets that may be used as diagnostic bio marker in aggressive TNBC patients for targeted therapy.