2. Academic Validation
  3. Cell-in-cell structure mediates in-cell killing suppressed by CD44

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

  • Cell Discov. 2022 Apr 19;8(1):35. doi: 10.1038/s41421-022-00387-1.
Yan Su  # 1 2,  Hongyan Huang  # 3,  Tianzhi Luo  # 2,  You Zheng 1,  Jie Fan 1,  He Ren 1 3,  Meng Tang 1 3,  Zubiao Niu 1,  Chenxi Wang 1,  Yuqi Wang 1,  Zhengrong Zhang 1,  Jianqing Liang 1,  Banzhan Ruan 1,  Lihua Gao 1,  Zhaolie Chen 1,  Gerry Melino 4 5,  Xiaoning Wang 6 7,  Qiang Sun 8
Affiliations

Affiliations

  • 1 Beijing Institute of Biotechnology, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, 20 Dongda Street, Beijing, China.
  • 2 CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei, China.
  • 3 Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing, China.
  • 4 Departments of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
  • 5 DZNE German Center for Neurodegenerative Diseases, Bonn, Germany.
  • 6 National Research Center of Geriatrics Diseases, Chinese PLA General Hospital, Beijing, China.
  • 7 School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
  • 8 Beijing Institute of Biotechnology, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, 20 Dongda Street, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 35436988 DOI: 10.1038/s41421-022-00387-1
Abstract

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.

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