LILRB3 and MHC class I interact to mechanically extrude transformed cells from the epithelial layer.

  • Major Finding: LILRB3 and MHC class I interact to mechanically extrude transformed cells from the epithelial layer.

  • Mechanism: Untransformed cell LILRB3–transformed cell MHC class I interactions induce SHP2 activation and filamin accumulation.

  • Impact: These insights into intrinsic elimination of precancerous cells may guide development of preventative therapies.

Using an immune surveillance–like function, epithelial cells are able to mechanically remove precancerous cells from the epithelial layer. The mechanism behind this recognition of premalignant cells and how it could be therapeutically exploited remains unknown. Ayukawa and colleagues identified an immunoglobulin-like domain-containing protein that is induced by mechanical stress and potentially interacts with major histocompatibility complex (MHC) class I. This protein was identified as suboptimal alteration recognizing protein [AltR or human leukocyte immunoglobulin-like receptor B3 (LILRB3)], and its expression was induced on normal cells when mixed with their transformed counterparts through a mechanical stress-induced RUNX2-dependent mechanism. LILRB3 on nontransformed cells was found to be required for apical extrusion, with expression of MHC class I on transformed cells also being necessary for this process to occur. Additional experiments indicated that these two surface proteins interact with one another through the α3 domain of MHC class I and the D1/D2 domain of LILRB3. Mechanistically, this interaction was necessary for extrusion of transformed cells, occurring through MHC class I–induced tyrosine phosphorylation of LILRB3 leading to activation of the SHP2–ROCK2 signaling pathway to ultimately result in cell extrusion through filamin accumulation. Tumorigenesis is suppressed upon interaction between these two receptors both in vitro and in vivo and, despite LILRB3 being a potential natural killer (NK) cell receptor, the reduction in tumorigenesis was independent of NK and T cells. Macrophages, however, were found to accumulate around the tumor, suggesting their involvement in clearance of the extruded tumor cells. Furthermore, patient data from those with skin and pancreatic cancer indicate high expression of LILRB3 is associated with better survival, although the exact function of LILRB3 remains to be fully examined. This study, therefore, indicates a novel role for LILRB3 and MHC class I outside of their normal immune function where they work to aid in reducing tumorigenesis through eliminating precancerous cells from the epithelial layer.

Ayukawa S, Kamoshita N, Nakayama J, Teramoto R, Pishesha N, Ohba K, et al. Epithelial cells remove precancerous cells by cell competition via MHC class I-LILRB3 interaction. Nat Immunol 2021;22:1391–402.

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