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Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Immune rejection of mouse tumors expressing mutated self
Fei Duan1, Yun Lin, Cailian Liu
1Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Abstract:
How the immune system recognizes and responds to mutations expressed by cancer cells is a critical issue for cancer immunology. Mutated self-polypeptides are particularly strong tumor-specific rejection antigens for natural tumor immunity, but we know remarkably little about T-cell responses to mutated self during tumor growth in vivo, including levels of response, kinetics, and correlates that predict tumor rejection. To address these questions, a mutated self-antigen, designated tyrosinase-related protein 1 (Tyrp1)-WM, derived from Tyrp1 was expressed in the poorly immunogenic, spontaneously arising B16 melanoma and the immunogenic, chemically induced LiHa fibrosarcoma. Syngeneic mice challenged with LiHa fibrosarcoma cells expressing Tyrp1-WM, but not native Tyrp1, induced specific CD8(+) and CD4(+) T-cell responses against defined mutated epitopes in tumor-draining lymph nodes and in tumors. Subsequently, specific CD8(+) T-cell responses contracted as a minority of tumors progressed. B16 melanomas expressing Tyrp1-WM induced minimal T-cell responses, and no tumor immunity was detected. Treatment with an agonist monoclonal antibody against glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) increased the level of CD8(+) T cells recognizing a peptide derived from the Tyrp1-WM sequence and the proportion of mice rejecting tumors. These results show that B16 tumors expressing mutations that generate strongly immunogenic epitopes naturally induce T-cell responses, which are insufficient to reject tumors. Immune modulation, such as inducing GITR signaling, is required to enhance CD8(+) T-cell responses to specific mutations and to lead to tumor rejection.
Insights
Cancer cells with mutations can trigger immune responses, but these are often insufficient for tumor rejection. Immune modulation, like glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) signaling, is needed to enhance T-cell responses and achieve tumor rejection.
Area of Science:
- Cancer Immunology
- Tumor Immunology
- Immunotherapy
Background:
- Understanding T-cell responses to cancer cell mutations is crucial for effective cancer immunology.
- Mutated self-polypeptides can act as potent tumor-specific rejection antigens, yet their in vivo dynamics remain poorly understood.
- Key aspects like response levels, kinetics, and predictive correlates for tumor rejection require further investigation.
Purpose of the Study:
- To investigate T-cell responses to mutated self-antigens during tumor growth in vivo.
- To determine if immune modulation can enhance anti-tumor immunity against specific mutations.
- To explore the potential of glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) signaling in cancer immunotherapy.
Main Methods:
- Expression of a mutated self-antigen (Tyrp1-WM) in B16 melanoma and LiHa fibrosarcoma models.
- Analysis of CD8(+) and CD4(+) T-cell responses in tumor-draining lymph nodes and tumors.
- Treatment with an agonist monoclonal antibody against GITR to assess immune modulation effects.
Main Results:
- LiHa fibrosarcoma expressing Tyrp1-WM induced specific CD8(+) and CD4(+) T-cell responses, but these contracted as tumors progressed.
- B16 melanomas expressing Tyrp1-WM elicited minimal T-cell responses and no detectable tumor immunity.
- GITR agonist treatment enhanced CD8(+) T-cell responses to Tyrp1-WM epitopes and increased tumor rejection rates.
Conclusions:
- Tumors expressing immunogenic mutated epitopes naturally induce T-cell responses, but these are often insufficient for rejection.
- Immune modulation, specifically through GITR signaling, is necessary to augment CD8(+) T-cell responses against tumor mutations.
- Targeting GITR offers a promising strategy to enhance anti-tumor immunity and achieve tumor rejection in certain cancers.
