Defective Localization With Impaired Tumor Cytotoxicity Contributes to the Immune Escape of NK Cells in Pancreatic Cancer Patients

In this study, we found that unlike CD8+ T and CD4+ T cells, pancreatic tumor cells are selectively resistant to NK cell-mediated immune surveillance. The very low frequency (<0.5%) of NK cells in tumors is a unique feature of patients with pancreatic cancer, as TILs isolated from patients with other solid tumor malignancies (breast, liver, lung, stomach, and colorectal cancers) show 3–10% of NK cell infiltration (40–45). Further in-depth analysis revealed that NK cells in patients with PDAC express significantly reduced CXCR2 on their surface, rendering them incapable of trafficking toward PDAC. In addition, poor engagement of NKG2D and DNAM-1 activating receptors in patients' NK cells explain the impaired killing of PDAC tumor cells. More importantly, circulating NK cells, upon reaching the hypoxic tumor microenvironment (pO2 ≤ 1.5%) failed to survive or proliferate, thereby contributing to overall specific immune escape of NK cells in such patients. Ours is the first report to demonstrate multiple NK cell-associated defects in newly developed patients. One of the major findings here is that peripheral NK cells lose the surface expression of CXCR2, which binds to CXCL chemokines released from PDAC cells. Circulating NK cells, however, do express CXCR4, but its ligand CXCL12 was not secreted by PDAC tumors. Hence, there are no apparent chemokine signals that could attract circulating NK cells to the PDAC tumors. Of note, Kreme...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research