NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

Abstract

Several evidences suggest that NK cells can patrol the body and eliminate tumors in their initial phases but may hardly control established solid tumors. Multiple factors, including the transition of tumor cells towards a proinvasive/prometastatic phenotype, the immunosuppressive effect of the tumor microenvironment, and the tumor structure complexity, may account for limited NK cell efficacy. Several putative mechanisms of NK cell suppression have been defined in these last years; conversely, the cross talk between NK cells and tumor cells undergoing different transitional phases remains poorly explored. Nevertheless, recent in vitro studies and immunohistochemical analyses on tumor biopsies suggest that NK cells could not only kill tumor cells but also influence their evolution. Indeed, NK cells may induce tumor cells to change the expression of HLA-I, PD-L1, or NKG2D-L and modulate their susceptibility to the immune response. Moreover, NK cells may be preferentially located in the borders of tumor masses, where, indeed, tumor cells can undergo Epithelial-to-Mesenchymal Transition (EMT) acquiring prometastatic phenotype. Finally, the recently highlighted role of HMGB1 both in EMT and in amplifying the recruitment of NK cells provides further hints on a possible effect of NK cells on tumor progression and fosters new studies on this issue.

Figure 1

New mechanism proposed for NK cell recruitment at melanoma tumor site. NK cells recognize melanoma cells through the interaction of NK activating receptors with their ligands (NKR-Ls) expressed on tumor cell (both depicted in dark blue). The resulting NK cell activation leads to the killing of melanoma cells (via perforin/granzyme B and induction of apoptosis) and to the active release of a chemotactic form of HMGB1 (green circles). Killed (apoptotic) cells passively release HMGB1 as oxidized molecule. However, this HMGB1 form has no chemotactic properties (purple circles). NK-derived reduced (i.e., all-thiol) HMGB1 can act as chemoattractant for activated NK cells through the engagement of RAGE (depicted in green), thus promoting their recruitment in the tumor microenvironment.