Human profilin 1 is a negative regulator of CTL mediated cell-killing and migration

Rouven Schoppmeyer1, Renping Zhao1, He Cheng2,3,4

  • 1Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.

Insights

Profilin1 (PFN1) negatively regulates cytotoxic T lymphocyte (CTL) function, impacting their migration and killing ability. PFN1 downregulation may enhance CTL anti-tumor activity in specific cancer contexts.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Actin dynamics are crucial for cytotoxic T lymphocyte (CTL) functions.
  • The role of actin-binding protein profilin1 (PFN1) in CTLs is not well understood.
  • PFN1 is the sole profilin family member expressed in human CD8+ T cells.

Purpose of the Study:

  • To elucidate the functional role of PFN1 in human CD8+ T cells.
  • To investigate PFN1's impact on CTL-mediated cytotoxicity and migration.
  • To assess PFN1's relevance in a tumor microenvironment and cancer patients.

Main Methods:

  • In vitro assays to assess CTL-mediated target cell elimination.
  • Analysis of PFN1's role in activation-induced lytic granule release and CTL migration.
  • Examination of actin structures at the immunological synapse (IS).
  • In vitro 3D matrix invasion assays under tumor microenvironment conditions.
  • Analysis of PFN1 expression in peripheral CD8+ T cells from pancreatic cancer patients.

Main Results:

  • PFN1 acts as a negative regulator of CTL-mediated target cell elimination.
  • PFN1 influences CTL migration velocity, protrusion patterns, and sustainability, but not persistence or protrusion rates.
  • PFN1 is involved in lytic granule release and actin remodeling at the IS.
  • PFN1 downregulation enhances CTL invasion into 3D matrices, independent of hydrogen peroxide-induced viability changes.
  • PFN1 expression is significantly decreased in CD8+ T cells of pancreatic cancer patients.

Conclusions:

  • PFN1 negatively regulates CTL cytotoxicity and impacts CTL migration and actin dynamics.
  • PFN1 modulation affects CTL invasion in simulated tumor microenvironments.
  • Decreased PFN1 expression in pancreatic cancer patients suggests a potential role in anti-tumor immunity.

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