Cell-in-cell structure mediates in-cell killing suppressed by CD44

Penetration of immune cells into tumor cells was believed to be immune-suppressive via cell-in-cell (CIC) mediated death of the internalized immune cells. We unexpectedly found that CIC formation largely led to the death of the host tumor cells, but not the internalized immune cells, manifesting typical features of death executed by NK cells; we named this in-cell killing which displays the efficacy superior to the canonical way of kiss-killing from outside. By profiling isogenic cells, CD44 on tumor cells was identified as a negative regulator of in-cell killing via inhibiting CIC formation. CD44 functions to antagonize NK cell internalization by reducing N-cadherin-mediated intercellular adhesion and by enhancing Rho GTPase-regulated cellular stiffness as well. Remarkably, antibody-mediated blockade of CD44 signaling potentiated the suppressive effects of NK cells on tumor growth associated with increased heterotypic CIC formation. Together, we identified CIC-mediated in-cell killing as a promising strategy for cancer immunotherapy.

Automated summary

Penetration of immune cells into tumor cells through cell-in-cell (CIC) formation leads to in-cell killing of the host tumor cells, showing superior efficacy compared to canonical kiss-killing from outside. CD44 on tumor cells functions as a negative regulator of in-cell killing by inhibiting CIC formation. Antibody-mediated blockade of CD44 signaling enhances the suppressive effects of NK cells on tumor growth.