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Tertiary Lymphoid Structures and Immunotherapy: Challenges and Opportunities.

Nancy H Ruddle1

  • 1Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA. nancy.ruddle@yale.edu.

Methods in Molecular Biology (Clifton, N.J.)
|November 11, 2024
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Summary

Tertiary lymphoid structures (TLS) in tumors can predict immunotherapy response but also risk autoimmunity. Manipulating TLS in cancer could improve treatment outcomes while minimizing side effects.

Keywords:
AutoimmunityImmune checkpoint inhibitorImmune-related adverse eventImmunotherapyLymphoid neogenesisTertiary lymphoid structureTumor-associated lymphoid structure

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Area of Science:

  • Immunology
  • Oncology
  • Pathology

Background:

  • Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates found in chronic inflammation, autoimmunity, infections, and cancer.
  • TLS share cellular and functional similarities with secondary lymphoid organs and can be associated with favorable outcomes in cancer patients.
  • Immune checkpoint inhibitors (ICI) have advanced cancer therapy but have limitations, including resistance and immune-related adverse events (irAEs) that resemble autoimmunity and can involve TLS.

Purpose of the Study:

  • To explore the dual role of tumor-associated tertiary lymphoid structures (TA-TLS) in cancer immunotherapy response and irAEs.
  • To investigate strategies for manipulating TA-TLS to optimize cancer immunotherapy efficacy and reduce autoimmunity.
  • To understand how the tumor microenvironment, specifically TLS, can be modulated for synergistic therapeutic effects.

Main Methods:

  • Review of existing literature on TLS, cancer immunology, and immunotherapy.
  • Analysis of the correlation between TA-TLS and response to ICI.
  • Exploration of potential strategies for modulating TLS, including directed delivery of cytokines, chemokines, and growth factors via vectors.

Main Results:

  • TA-TLS are associated with positive responses to immunotherapy but also with increased susceptibility to irAEs.
  • The presence and characteristics of TA-TLS suggest a complex interplay between anti-tumor immunity and autoimmunity.
  • Strategies targeting TLS composition and function hold promise for enhancing immunotherapy efficacy.

Conclusions:

  • TLS represent a critical component of the tumor immune microenvironment with implications for both therapeutic response and adverse events.
  • Modulating TLS offers a potential avenue to improve the balance between anti-tumor immunity and self-tolerance in cancer patients treated with immunotherapy.
  • Future research should focus on targeted manipulation of TLS to achieve synergistic effects with immunotherapy and minimize irAEs.