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Tumors evade immune cytotoxicity by altering the surface topology of NK cells

Xiaohu Zheng1,2,3, Zhuanghao Hou4,5, Yeben Qian6

  • 1Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. ustczxh@ustc.edu.cn.

Nature Immunology
|March 24, 2023
PubMed

Insights

Tumors disrupt natural killer (NK) cell membrane structure, impairing their ability to kill cancer cells. Restoring sphingomyelin levels shows promise for effective cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Biology

Background:

  • Immunotherapy response rates vary widely, indicating incomplete understanding of tumor immune evasion strategies.
  • Natural killer (NK) cells are crucial for innate immunity against tumors.

Purpose of the Study:

  • To investigate the membrane topology of intratumoral NK cells in liver cancer.
  • To elucidate the mechanisms by which tumors impair NK cell function.
  • To explore therapeutic strategies targeting NK cell dysfunction.

Main Methods:

  • Comparative analysis of NK cell membrane protrusions in tumor-infiltrating, peritumoral, and peripheral blood samples from liver cancer patients.
  • Assessment of sphingomyelin (SM) content and serine metabolism in intratumoral NK cells.
  • Experimental inhibition of SM biosynthesis in peripheral NK cells to model intratumoral NK cell defects.
  • Evaluation of targeting sphingomyelinase as a therapeutic approach.

Main Results:

  • Intratumoral NK cells exhibit reduced membrane protrusions compared to peripheral and peritumoral NK cells.
  • This altered membrane topology hinders NK cell recognition of tumor cells, synapse formation, and cytotoxic activity.
  • Decreased SM levels in intratumoral NK cells are linked to dysregulated serine metabolism.
  • Inhibiting SM biosynthesis in healthy NK cells replicated the functional deficits observed in tumor-infiltrating NK cells.
  • Targeting sphingomyelinase demonstrated significant antitumor efficacy.

Conclusions:

  • Tumor-induced alterations in NK cell membrane topology, driven by sphingomyelin dysregulation, compromise anti-tumor immunity.
  • Restoring sphingomyelin levels or inhibiting sphingomyelinase represents a promising therapeutic strategy for liver cancer immunotherapy, potentially enhancing checkpoint blockade efficacy.

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