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Bystander elimination of antigen loss variants in established tumors
Michael T Spiotto1, Donald A Rowley, Hans Schreiber
1Department of Pathology and The Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA. mspiotto@midway.uchicago.edu
Abstract:
Cancers express antigens that are targets for specific cytotoxic T lymphocytes (CTLs). However, cancer cells are genetically unstable. Consequently, sub-populations of cancer cells that no longer express the target antigen may escape destruction by CTLs and grow progressively. We show that cytotoxic T cells indirectly eliminate these antigen loss variants (ALVs) in a model system when the parental cancer cells express sufficient antigen to be effectively cross-presented by the tumor stroma. When the parental tumor expressed lower levels of antigen, cytotoxic T cells eradicated the antigen-positive parental cancer cells, but the ALVs escaped, grew and killed the host. By contrast, when the parental tumor expressed higher levels of antigen, cytotoxic T cells eradicated not only the parental cancer cells but also the ALVs. This 'bystander' elimination of ALVs required stromal cells expressing major histocompatibility complex (MHC) molecules capable of presenting the antigen, and occurred in tumors showing evidence of stromal destruction. ALVs were apparently eliminated indirectly when tumor-specific CTLs killed stromal cells that were cross-presenting antigen produced by and released from antigen-positive cancer cells. These results highlight the general importance of targeting the tumor stroma to prevent the escape of variant cancer cells.
Insights
Cytotoxic T lymphocytes (CTLs) can eliminate cancer antigen loss variants (ALVs) indirectly. Targeting tumor stroma is crucial to prevent cancer immune escape and improve therapy efficacy.
Area of Science:
- Immunology
- Cancer Biology
- Tumor Microenvironment
Background:
- Cancer cells express antigens recognized by cytotoxic T lymphocytes (CTLs).
- Genetic instability in cancer leads to antigen loss variants (ALVs) that evade CTL destruction.
- Effective CTL responses are critical for controlling tumor progression.
Purpose of the Study:
- To investigate the mechanisms by which CTLs eliminate antigen loss variants (ALVs).
- To determine the role of tumor antigen expression levels and tumor stroma in ALV elimination.
- To explore strategies for preventing cancer immune escape.
Main Methods:
- Utilized a model system to study cancer cell-tumor stroma interactions.
- Manipulated antigen expression levels on parental cancer cells.
- Assessed CTL-mediated elimination of both parental cancer cells and ALVs.
- Analyzed the role of stromal cells and MHC molecule expression in antigen cross-presentation.
Main Results:
- Sufficient parental tumor antigen expression enabled indirect elimination of ALVs via cross-presentation by the tumor stroma.
- Low antigen expression led to CTLs eradicating parental cells but ALVs escaping and causing host death.
- High antigen expression resulted in CTLs eliminating both parental cells and ALVs.
- Bystander elimination of ALVs required MHC-expressing stromal cells and occurred during stromal destruction.
Conclusions:
- Indirect elimination of ALVs by CTLs is possible through cross-presentation by tumor stroma.
- Tumor antigen levels significantly impact the efficacy of CTLs against ALVs.
- Targeting the tumor stroma is a potential strategy to overcome cancer immune escape mediated by ALVs.
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