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Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Eomesodermin is required for antitumor immunity mediated by 4-1BB-agonist immunotherapy
Chang Song1, Kavitha Sadashivaiah1, Aki Furusawa1
1Program in Oncology; Greenebaum Cancer Center; Center for Stem Cell Research and Regenerative Medicine; Department of Medicine; University of Maryland School of Medicine; Baltimore, MD USA.
Abstract:
CD8+ T cells in progressing tumors frequently fail to mount an effective antitumor response often in association with the expression of inhibitory receptors, including programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (Lag3). Using a lymphoma tumor model, we demonstrate that tumor-infiltrating CD8+ T cells from growing tumors co-express inhibitory receptors and co-stimulatory receptors, including 4-1BB (TNFRSF9) as well as high levels of 2 transcription factors, Eomesodermin (Eomes) and T-bet (Tbx21), critical determinants of CD8+ T cell fate. Immunotherapy with an agonistic anti-4-1-BB antibody altered the ratio of Eomes to T-bet expression in tumor-infiltrating CD8+ T cells by increasing Eomes and decreasing T-bet expression. 4-1BB-agonist immunotherapy was also associated with downregulated expression of the inhibitory receptors PD-1 and Lag3 on tumor-infiltrating CD8+ T cells, a molecular phenotype associated with subsequent attenuation of tumor growth. Furthermore, 4-1BB-agonist immunotherapy failed to effect tumor progression in mice with Eomes deficient T cells. However, upon resumption of tumor growth, tumor-infiltrating CD8+ T cells from treated animals continued to express high levels of Eomes as well as elevated levels of the inhibitory receptors PD-1 and Lag3. Our data suggest that tumor-infiltrating CD8+ T cells are poised between activation and inhibition as dictated by expression of both co-stimulatory receptors and inhibitory receptors and demonstrate that T cell expression of Eomes is necessary, but not sufficient, for efficacious 4-1BB-agonist-mediated immunotherapy.
Insights
Anti-4-1-BB immunotherapy enhances CD8+ T cell responses against tumors by altering transcription factor balance and reducing inhibitory receptors. However, Eomesodermin (Eomes) expression is crucial for this immunotherapy
Area of Science:
- Immunology
- Cancer Biology
- T cell biology
Background:
- CD8+ T cells in tumors often show impaired antitumor activity due to inhibitory receptors like PD-1 and Lag3.
- Tumor-infiltrating CD8+ T cells express both inhibitory and co-stimulatory receptors, alongside key transcription factors Eomes and T-bet.
Purpose of the Study:
- To investigate the role of 4-1BB co-stimulation in modulating CD8+ T cell function within the tumor microenvironment.
- To determine the necessity of Eomesodermin (Eomes) for effective anti-4-1-BB immunotherapy.
Main Methods:
- Utilized a lymphoma tumor model in mice.
- Administered agonistic anti-4-1-BB antibody immunotherapy.
- Analyzed transcription factor (Eomes, T-bet) and receptor (PD-1, Lag3, 4-1BB) expression on tumor-infiltrating CD8+ T cells.
- Assessed tumor growth and T cell function in wild-type and Eomes-deficient mice.
Main Results:
- Anti-4-1-BB therapy increased Eomes and decreased T-bet expression in CD8+ T cells, alongside reduced PD-1 and Lag3 levels.
- This immunotherapy led to attenuated tumor growth.
- Eomes-deficient T cells failed to respond to anti-4-1-BB immunotherapy, halting tumor progression.
- Sustained Eomes expression and elevated PD-1/Lag3 were observed in T cells from regrowing tumors after treatment.
Conclusions:
- Tumor-infiltrating CD8+ T cells exist in a state of activation/inhibition balance influenced by receptor expression.
- Eomesodermin (Eomes) expression is essential, though not sufficient, for successful 4-1BB-agonist immunotherapy.
- 4-1BB-agonist immunotherapy shows potential but requires further understanding of T cell intrinsic factors like Eomes for optimal efficacy.
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