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Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality

Esther Schoutrop1, Stefanie Renken1, Isabella Micallef Nilsson1

  • 1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Oncoimmunology
|July 28, 2022
PubMed

Insights

Chimeric antigen receptor (CAR) T cell therapy shows promise for solid tumors. This study found CD28-costimulated CAR T cells are more effective than 4-1BB-costimulated ones, identifying trogocytosis and LAG-3 as key challenges.

Area of Science:

  • Immunotherapy
  • Oncology
  • Cellular Biology

Background:

  • Chimeric antigen receptor (CAR) T cell therapy faces challenges in solid tumors due to the tumor microenvironment and antigen heterogeneity.
  • Mesothelin (MSLN) is a promising target for CAR T cell therapy in solid malignancies like ovarian cancer.
  • Understanding in vitro mechanisms is crucial for improving MSLN-CAR T cell therapy outcomes.

Purpose of the Study:

  • To compare the efficacy of CD28-costimulated (M28z) versus 4-1BB-costimulated (MBBz) MSLN-CAR T cells.
  • To investigate mechanisms limiting MSLN-CAR T cell functionality in solid tumors.
  • To identify potential strategies for enhancing CAR T cell therapy.

Main Methods:

  • Comparison of cytolytic capacity of M28z and MBBz CAR T cells against tumor spheroids.
  • Identification of CAR-mediated trogocytosis as a factor affecting CAR T cell therapy.
  • Analysis of the relationship between antigen-dependent LAG-3 upregulation and CAR T cell function.

Main Results:

  • CD28-costimulated MSLN-CAR T cells (M28z) exhibited superior cytolytic activity compared to 4-1BB-costimulated MSLN-CAR T cells (MBBz).
  • M28z CAR T cells demonstrated enhanced efficacy against tumor spheroids with heterogeneous MSLN expression.
  • CAR-mediated trogocytosis was identified as a mechanism causing fratricide and contributing to antigen heterogeneity.
  • Antigen-dependent LAG-3 upregulation was correlated with reduced CAR T cell functionality.

Conclusions:

  • CD28-costimulated MSLN-CAR T cells offer enhanced anti-tumor activity.
  • CAR-mediated trogocytosis and LAG-3 upregulation represent significant hurdles for MSLN-CAR T cell therapy.
  • Findings support the development of combinatorial treatment strategies to overcome therapeutic bottlenecks.
Keywords:
CAR T cellsfratricide killingimmune escapemesothelinovarian cancertrogocytosis

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