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Updated: May 13, 2026
Purification and Expansion of Mouse Invariant Natural Killer T Cells for in vitro and in vivo Studies
Published on: February 15, 2021
IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers
Bin Zhang1, Theodore Karrison, Donald A Rowley
1Department of Pathology and Committee on Immunology, University of Chicago, Chicago, Illinois, USA. zhangb3@uthscsa.edu
Abstract:
Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell-based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma. Here, we showed that IFN-gamma and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs. In addition, both BM- and non-BM-derived stromal cells were required to express TNF receptors and IFN-gamma receptors for the elimination of ALVs. Although IFN-gamma and TNF were not required by CTLs for perforin-mediated killing of antigen-expressing tumor cells, the strong inference is that tumor antigen-specific CTLs must secrete IFN-gamma and TNF for destruction of tumor stroma. Therefore, bystander killing of ALVs may result from IFN-gamma and TNF acting on tumor stroma.
Insights
Cytotoxic T lymphocytes (CTLs) eliminate tumors, including antigen-loss variants (ALVs), by secreting IFN-gamma and TNF. These cytokines are crucial for destroying tumor stroma, enabling bystander killing of ALVs.
Area of Science:
- Immunology
- Oncology
- Cancer immunotherapy
Background:
- Tumors can evade immune responses by losing antigens, leading to antigen-loss variants (ALVs).
- ALVs pose a significant challenge to T cell-based cancer immunotherapy.
- Effective cancer elimination may require targeting both tumor cells and the tumor stroma.
Purpose of the Study:
- To investigate the role of CTL-secreted cytokines in eliminating established tumors, including ALVs.
- To determine the mechanisms by which CTLs overcome immune escape strategies like antigen loss.
- To elucidate the contribution of tumor stroma to the efficacy of cancer immunotherapy.
Main Methods:
- Utilized a mouse model to study tumor elimination by CTLs.
- Assessed the impact of IFN-gamma and TNF on tumor clearance, including ALVs.
- Investigated the requirement of TNF and IFN-gamma receptors on stromal cells for tumor elimination.
Main Results:
- CTL-secreted IFN-gamma and TNF were essential for eliminating established mouse tumors, including ALVs.
- Stromal cells expressing TNF and IFN-gamma receptors were necessary for ALV elimination.
- IFN-gamma and TNF were not required for CTL-mediated killing of antigen-expressing tumor cells but are inferred to be critical for stroma destruction.
Conclusions:
- Tumor antigen-specific CTLs secrete IFN-gamma and TNF, which are crucial for destroying the tumor stroma.
- This cytokine-mediated destruction of stroma may facilitate the bystander killing of ALVs.
- Targeting tumor stroma alongside tumor cells represents a potential strategy to overcome immune escape in cancer immunotherapy.
