Abstract
Several studies have demonstrated that the antitumor activities of both T and natural killer (NK) effector populations are limited by the immunosuppressive strategies of tumors. In several malignant transformations, the expression of HLA-G by tumor cells rises dramatically, rendering them strongly immunosuppressive. In this study, we postulated that the absence of HLA-G receptors would prevent the immunosuppressive effects of both soluble and membrane-bound HLA-G. Thus, we investigated the therapeutic potential of effector NK cells genetically modified to downregulate the expression of ILT2 (HLA-G receptor) on their cell surfaces. We have shown that the proliferation of modified NK is still dependent on stimulation signals (no malignant transformation). ILT2- NK cells proliferate, migrate, and eliminate HLA-G negative targets cells to the same extent parental NK cells do. However, in the presence of HLA-G positive tumors, ILT2- NK cells exhibit superior proliferation, conjugate formation, degranulation, and killing activities compared to parent NK cells. We tested the effectiveness of ILT2- NK cells in vivo using a xenograft cancer model and found that silencing ILT2 rescued their anti-tumor activity.We believe that combining ILT2- NK cells with existing therapeutic strategies will strengthen the antitumor response in cancer patients.
Highlights
Expressed in immune privileged sites such as the thymus and trophoblast, HLA-G has been detected on numerous malignant cell types
ILT2 is expressed on most immune cells, and ILT4 is only found on monocytes and dendritic cells
ILT2 binds dimers of α3 HLA-G domains associated with β2-microglobulin (B2M) and ILT4 binds dimers of α3 HLA-G domains free of B2M
Summary
Expressed in immune privileged sites such as the thymus and trophoblast, HLA-G has been detected on numerous malignant cell types. It is expressed on many blood tumor types including, chronic lymphocytic leukemia, acute myeloid tumor, and multiple myeloma [1, 2], and on solid tumors like lymphomas [3], melanoma [4], neuroblastoma [5], breast cancer [6], and lung cancer [7]. Clinical data have shown that HLA-G is associated with poor prognosis when expressed on lymphomas [9], leukemic cells [10], breast cancers [11], glioblastoma [12], and multiple myeloma [13].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call