Densely Granulated Murine NK Cells Eradicate Large Solid Tumors

Overview

Journal Cancer Res

Specialty Oncology

Date 2012 Mar 1

PMID 22374983

Citations 34

Authors

Rebecca B Liu

Boris Engels

Ainhoa Arina

Karin Schreiber

Elizabeth Hyjek

Andrea Schietinger

David C Binder

Eric Butz

Thomas Krausz

Donald A Rowley

Bana Jabri

Hans Schreiber

Affiliations

Soon will be listed here.

Abstract

Natural killer (NK) cells inhibit early stages of tumor formation, recurrence, and metastasis. Here, we show that NK cells can also eradicate large solid tumors. Eradication depended on the massive infiltration of proliferating NK cells due to interleukin 15 (IL-15) released and presented by the cancer cells in the tumor microenvironment. Infiltrating NK cells had the striking morphologic feature of being densely loaded with periodic acid-Schiff-positive, diastase-resistant granules, resembling uterine NK cells. Perforin-mediated killing by these densely granulated NK cells was essential for tumor eradication. Expression of the IL-15 receptor α on cancer cells was needed to efficiently induce granulated NK cells, and expression on host stromal cells was essential to prevent tumor relapse after near complete destruction. These results indicate that IL-15 released at the cancer site induces highly activated NK cells that lead to eradication of large solid tumors.

Citing Articles

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Wessel R, Ageeb N, Obeid J, Mauldin I, Goundry K, Hanson G J Immunother Cancer. 2024; 12(9).

PMID: 39299754 PMC: 11418484. DOI: 10.1136/jitc-2024-009126.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Wessel R, Ageeb N, Obeid J, Mauldin I, Goundry K, Hanson G bioRxiv. 2024; .

PMID: 38979183 PMC: 11230195. DOI: 10.1101/2024.02.20.581048.

Advancements in Cancer Immunotherapies.

Roy R, Singh S, Misra S Vaccines (Basel). 2023; 11(1).

PMID: 36679904 PMC: 9861770. DOI: 10.3390/vaccines11010059.

A Mouse Model of Celiac Disease.

Abadie V, Khosla C, Jabri B Curr Protoc. 2022; 2(8):e515.

PMID: 35994521 PMC: 10203737. DOI: 10.1002/cpz1.515.

The 'Danse Macabre'-Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes.

Hadjigol S, Shah B, OBrien-Simpson N Front Immunol. 2022; 13:894021.

PMID: 35784290 PMC: 9243430. DOI: 10.3389/fimmu.2022.894021.

References

Carson W, Giri J, Lindemann M, Linett M, Ahdieh M, Paxton R . Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994; 180(4):1395-403. PMC: 2191697. DOI: 10.1084/jem.180.4.1395. View

Arina A, Murillo O, Dubrot J, Azpilikueta A, Gabari I, Perez-Gracia J . Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells. Gene Ther. 2008; 15(7):473-83. DOI: 10.1038/gt.2008.4. View

DePaolo R, Abadie V, Tang F, Fehlner-Peach H, Hall J, Wang W . Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011; 471(7337):220-4. PMC: 3076739. DOI: 10.1038/nature09849. View

Jondal M, Pross H . Surface markers on human b and t lymphocytes. VI. Cytotoxicity against cell lines as a functional marker for lymphocyte subpopulations. Int J Cancer. 1975; 15(4):596-605. DOI: 10.1002/ijc.2910150409. View

Gasser S, Orsulic S, Brown E, Raulet D . The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 2005; 436(7054):1186-90. PMC: 1352168. DOI: 10.1038/nature03884. View

Tasaki K, Yoshida Y, Miyauchi M, Maeda T, Takenaga K, Kouzu T . Transduction of murine colon carcinoma cells with interleukin-15 gene induces antitumor effects in immunocompetent and immunocompromised hosts. Cancer Gene Ther. 2000; 7(2):255-61. DOI: 10.1038/sj.cgt.7700112. View

Meazza R, Lollini P, Nanni P, De Giovanni C, Gaggero A, Comes A . Gene transfer of a secretable form of IL-15 in murine adenocarcinoma cells: effects on tumorigenicity, metastatic potential and immune response. Int J Cancer. 2000; 87(4):574-81. View

Stallmach T, Ehrenstein T, Isenmann S, Muller C, Hengartner H, Kagi D . The role of perforin-expression by granular metrial gland cells in pregnancy. Eur J Immunol. 1995; 25(12):3342-8. DOI: 10.1002/eji.1830251221. View

Croy B, Esadeg S, Chantakru S, van den Heuvel M, Paffaro V, He H . Update on pathways regulating the activation of uterine Natural Killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus. J Reprod Immunol. 2003; 59(2):175-91. DOI: 10.1016/s0165-0378(03)00046-9. View

10.

Phillips J, Lanier L . Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis. J Exp Med. 1986; 164(3):814-25. PMC: 2188384. DOI: 10.1084/jem.164.3.814. View

11.

Kiessling R, Klein E, Wigzell H . "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975; 5(2):112-7. DOI: 10.1002/eji.1830050208. View

12.

Kroemer A, Xiao X, Degauque N, Edtinger K, Wei H, Demirci G . The innate NK cells, allograft rejection, and a key role for IL-15. J Immunol. 2008; 180(12):7818-26. DOI: 10.4049/jimmunol.180.12.7818. View

13.

Stoklasek T, Schluns K, Lefrancois L . Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol. 2006; 177(9):6072-80. PMC: 2847275. DOI: 10.4049/jimmunol.177.9.6072. View

14.

Spiotto M, Rowley D, Schreiber H . Bystander elimination of antigen loss variants in established tumors. Nat Med. 2004; 10(3):294-8. DOI: 10.1038/nm999. View

15.

Papadimitriou J, Drachenberg C, Brenner D, Newkirk C, Trump B, Silverberg S . "Thanatosomes": a unifying morphogenetic concept for tumor hyaline globules related to apoptosis. Hum Pathol. 2001; 31(12):1455-65. DOI: 10.1053/hupa.2000.20376. View

16.

Grabstein K, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V . Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994; 264(5161):965-8. DOI: 10.1126/science.8178155. View

17.

Barber E, Pollard J . The uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol. 2003; 171(1):37-46. DOI: 10.4049/jimmunol.171.1.37. View

18.

Pegram H, Haynes N, Smyth M, Kershaw M, Darcy P . Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. Cancer Immunol Immunother. 2010; 59(8):1235-46. PMC: 11030891. DOI: 10.1007/s00262-010-0848-7. View

19.

Guerra N, Tan Y, Joncker N, Choy A, Gallardo F, Xiong N . NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008; 28(4):571-80. PMC: 3528789. DOI: 10.1016/j.immuni.2008.02.016. View

20.

Yajima T, Nishimura H, Wajjwalku W, Harada M, Kuwano H, Yoshikai Y . Overexpression of interleukin-15 in vivo enhances antitumor activity against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response. Int J Cancer. 2002; 99(4):573-8. DOI: 10.1002/ijc.10395. View