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

Abstract

Tumor-infiltrating lymphocytes (TILs), found in patients with advanced pancreatic ductal adenocarcinoma (PDAC), are shown to correlate with overall survival (OS) rate. Although majority of TILs consist of CD8 + /CD4 + T cells, the presence of NK cells and their role in the pathogenesis of PDAC remains elusive. We performed comprehensive analyses of TIL, PBMC, and autologous tumor cells from 80 enrolled resectable PDAC patients to comprehend the NK cell defects within PDAC. Extremely low frequencies of NK cells (<0.5%) were found within PDAC tumors, which was attributable not to the low expression of tumor chemokines, but to the lack of chemokine receptor, CXCR2. Forced expression of CXCR2 in patients' NK cells rendered them capable of trafficking into PDAC. Furthermore, NK cells exhibited impaired cell-mediated killing of autologous PDAC cells, primarily due to insufficient ligation of NKG2D and DNAM-1, and failed to proliferate within the hypoxic tumor microenvironment. Importantly, these defects could be overcome by ex-vivo stimulation of NK cells from such patients. Importantly, when the proliferative capacity of NK cells in vitro was used to stratify patients on the basis of cell expansion, patients whose NK cells proliferated <250-fold experienced significantly lower DFS and OS than those with ≥250-fold. Ex-vivo activation of NK cells restored tumor trafficking and reactivity, hence provided a therapeutic modality while their fold expansion could be a potentially significant prognostic indicator of OS and DFS in such patients.

CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma

“…TGF‐β1 inhibits cytokine secretion and cytotoxicity of NK cells [15–18,27]. NK cell function was impaired, which had been widely observed in patients with advanced cancer [29–31]. Consistent with previous data, we found that plasma TGF‐β1 levels were obviously elevated in patients with HCCBC, albeit only slightly higher in adjacent tumor tissues than in tumors and healthy tissues.…”

The Immune Microenvironment in Pancreatic Cancer

“…Aside from that, it has been found that the abundance of activated pancreatic stellate cells in the stroma of pancreatic cancer can diminish NK cell functions in the local tumor microenvironment [ 91 ]. Moreover, it was demonstrated that PDAC-NK cells exhibit an impaired tumor localization that was associated with the downregulation of the chemokine receptor CXCR2 [ 92 ]. Therefore, PDAC tumors show an extremely low frequency of NK cell infiltration (<0.5%) counteracting tumor cell elimination.…”

“…Therefore, PDAC tumors show an extremely low frequency of NK cell infiltration (<0.5%) counteracting tumor cell elimination. Of note, the in vitro proliferation rate of isolated tumor-infiltrating NK cells was associated with a longer overall survival [ 92 ].…”

“…However, as described for other cancers [ 100 ], it seems possible to restore the restricted cytotoxicity of tumor-associated NK cells upon ex vivo stimulation and proliferation. Of note, the tumor cell killing efficacy mediated by these patient-derived NK cells was comparable to the efficacy of NK cells isolated from healthy donors [ 92 ], drawing interest to immune therapies aimed at restoring NK cell functions [ 101 , 102 ]. In the same line, it was reported that ex vivo expanded and antibody-activated NK cells that were adoptively transferred to patients exhibited potent IFNγ secretion and significant anti-tumor activity against pancreatic cancer cells [ 103 ].…”

The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

“…Thus, the response of patients with PDAC to immunotherapy is overall limited [ 6 ]. However increasing pieces of evidence suggest that the restoration of NK cell activity in the tumor microenvironment (TME) may interfere with PDAC progression [ 7 , 8 ] exerting direct cytotoxicity and orchestrating the anti-tumor immune response.…”