The destiny of natural killer cells in the tumor microenvironment : to be suppressed or activated?

In the mid-70s, the term “natural” was used based on the functional properties of NK cells where they recognize and lyse certain tumor cells without requirement of prior immunization. Although NK cells are “natural” in their targeting of tumors, their responses in the tumor microenvironment have been very challenging to determine. The tumor microenvironment is known to consist of a heterogeneous population of cells and secreted factors.

The failure in the immune surveillance may in part be due to sustained immunological selection pressure on tumor cells resulting in the development of tumor escape variants that are effectively invisible to the immune system. On the other hand it can be due to the complex network of immune suppressive compartments in the tumor microenvironment.

We have studied NK cell activity in the tumor microenvironment. The study was divided into two parts; 1) how to augment NK cell activity against tumor cells, and 2) examine the suppression of NK cells in the tumor microenvironment.

A novel proteasome inhibitor (b-AP15) was found to sensitize tumor cells of different origin to NK cell and T cell- TRAIL mediated killing. Combined therapy with b-AP15 and infusion of NK cells and T cells in animals resulted in reduced tumor progression and prolonged survival. We also found that enhancement of TRAIL expression on NK cells could augment their cytotoxicity against tumors. Such action was possible when NK cells were interacting with monocytes that were manipulated with a bisphosphonate called Zoledronic Acid to produce IFN-γ.

Studies on suppression of NK cells involved the outcome of interaction between NK cells and dendritic cells (DC) or myeloid-derived suppressor cells (MDSC), both in vitro and in cancer patients. We found that both DC and MDSCs suppress NK cell responses in patients with cancer. STAT-3 phosphorylation status in DC determined NK cell responses. Furthermore, the crosstalk between DC and NK cells was regulated through production of LTA, IL-12, and TGF-β. We found that prostaglandin E2 (PGE2) converts healthy monocytes to MDSC-like cells. Similar to patient-derived MDSCs, PGE2-treated monocytes showed increased phosphorylation of p38MAPK/ERK and suppressed NK cell responses by the production of TGF-β.

In this thesis, new strategies to improve NK cell-based therapy have been suggested and new findings about the mechanisms of suppressing NK cells in the tumor microenvironment have been revealed.

List of scientific papers

I. Sarhan D, Wennerberg E, D'Arcy P, Gurajada D, Linder S, Lundqvist A. A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. Cancer Immunol Immunother. 2013;62(8):1359-68
https://doi.org/10.1007/s00262-013-1439-1

II. Sarhan D, D'Arcy P, Wennerberg E, Lidén M, Hu J, Winqvist O, Rolny C, Lundqvist A. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. Eur J Immunol. 2013; 43(1):249-57
https://doi.org/10.1002/eji.201242735

III. Sarhan D, Palma M, Mao M, Adamson L, Kiessling R, Mellstedt H, Österborg A and Lundqvist A. Regulation of NK cell responses by dendritic cells via lymphotoxin-alpha, interleukin-12, and tumor growth factor-beta; implications for development of DC vaccines against cancer. [Manuscript]

IV. Sarhan D, Mao Y, Steven A, Seliger B, Kiessling R and Lundqvist A. Myeloid-derived suppressor cells inhibit NK cell activity through prostaglandin-E2 regulated TGF-β production. [Manuscript]