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

• Published in: Cell discovery Vol. 8; no. 1; pp. 35 - 18
• Main Authors: Su, Yan, Huang, Hongyan, Luo, Tianzhi, Zheng, You, Fan, Jie, Ren, He, Tang, Meng, Niu, Zubiao, Wang, Chenxi, Wang, Yuqi, Zhang, Zhengrong, Liang, Jianqing, Ruan, Banzhan, Gao, Lihua, Chen, Zhaolie, Melino, Gerry, Wang, Xiaoning, Sun, Qiang
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 19.04.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/250/580; 631/67/1059/2325; 631/80/82/23; Apoptosis; Biomedical and Life Sciences; Cadherins; Cancer immunotherapy; CD44 antigen; Cell adhesion; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell death; Cell Physiology; Cloning; Cytology; Immunotherapy; Internalization; Life Sciences; Liver cancer; Morphology; N-Cadherin; Natural killer cells; Stem Cells; Tumor cells
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/s41421-022-00387-1

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.