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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies [1, 2]
Representative flow cytometry data with gating strategies (Figures S1, S2) and individual dot graphs (Figure 1A) indicate that patients with pancreatic ductal adenocarcinoma (PDAC) show broad ranges of CD56+CD3− NK cells (27.55 ± 14.8%) in PBMCs compared to healthy donors (HD); very little NK cells (0.34 ± 0.50%) were found within Tumor-infiltrating lymphocytes (TILs) of such patients
Our data demonstrate that the number of NK cells in the PDAC patients were not found to be significantly smaller than that of HD controls while over 50% of reduction of B, CD4 T, and CD8 T cells were reduced in the patients (Figure 1B, bottom)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies [1, 2]. Most of the activated T cells, localized to PDAC, express an array of co-inhibitory receptors, including PD-1, LAG-3, TIM3, and CTLA-4, which can induce tolerance and exhaustion of Antigen-specific T cells after the initial recognition of tumors [9, 18,19,20,21]. It has been shown previously that progression of pancreatic cancer is closely associated with dysfunctional circulating NK cells in PBMC [27]. The presence of NK cells within pancreatic tumors and their role in the progression of PDAC remains unclear. To address these issues, we obtained tumor and peripheral blood samples from such patients undergoing surgical resection, and performed a detailed analysis of NK cell frequency and their proliferation profile. We isolated tumor cells from the patients to assess anti-tumor function of the NK cells in autologous settings, and attempted to correlate these parameters with clinically annotated findings
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