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

Seon Ah Lim, Jungwon Kim, Seunghyun Jeon, Min Hwa Shin, Joonha Kwon, Tae Jin Kim, Kyungtaek Im, Youngmin Han, Wooil Kwon, Sun Whe Kim, Cassian Yee, Seong Jin Kim, Jin Young Jang, Kyung-Mi Lee

Research output: Contribution to journalArticle

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.

Original languageEnglish
Number of pages1
JournalFrontiers in immunology
Volume10
DOIs
Publication statusPublished - 2019 Jan 1

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Pancreatic Neoplasms
Natural Killer Cells
Adenocarcinoma
Tumor-Infiltrating Lymphocytes
Neoplasms
Tumor Microenvironment
Survival
Chemokine Receptors
Chemokines
Ligation
Survival Rate
T-Lymphocytes

Keywords

  • cancer immunobiology
  • cellular immunology
  • chemokines
  • immunotherapy
  • pancreatic cancer

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Defective Localization With Impaired Tumor Cytotoxicity Contributes to the Immune Escape of NK Cells in Pancreatic Cancer Patients. / Lim, Seon Ah; Kim, Jungwon; Jeon, Seunghyun; Shin, Min Hwa; Kwon, Joonha; Kim, Tae Jin; Im, Kyungtaek; Han, Youngmin; Kwon, Wooil; Kim, Sun Whe; Yee, Cassian; Kim, Seong Jin; Jang, Jin Young; Lee, Kyung-Mi.

In: Frontiers in immunology, Vol. 10, 01.01.2019.

Research output: Contribution to journalArticle

Lim, Seon Ah ; Kim, Jungwon ; Jeon, Seunghyun ; Shin, Min Hwa ; Kwon, Joonha ; Kim, Tae Jin ; Im, Kyungtaek ; Han, Youngmin ; Kwon, Wooil ; Kim, Sun Whe ; Yee, Cassian ; Kim, Seong Jin ; Jang, Jin Young ; Lee, Kyung-Mi. / Defective Localization With Impaired Tumor Cytotoxicity Contributes to the Immune Escape of NK Cells in Pancreatic Cancer Patients. In: Frontiers in immunology. 2019 ; Vol. 10.
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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.",
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AU - Lim, Seon Ah

AU - Kim, Jungwon

AU - Jeon, Seunghyun

AU - Shin, Min Hwa

AU - Kwon, Joonha

AU - Kim, Tae Jin

AU - Im, Kyungtaek

AU - Han, Youngmin

AU - Kwon, Wooil

AU - Kim, Sun Whe

AU - Yee, Cassian

AU - Kim, Seong Jin

AU - Jang, Jin Young

AU - Lee, Kyung-Mi

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N2 - 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.

AB - 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.

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KW - cellular immunology

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KW - immunotherapy

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