Cancer immunology, immunotherapy : CII · 2026
Targeting Blimp-1 in T cells results in activation of T-bet-mediated control of immunosuppression in lung cancer.
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Finotto Susetta, Chiriac Mircea T, Krammer Susanne, Yang Zuqin, Neurath Laura, Geppert Carol I, Nendel Elvedina, Trump Sonja, Geiger Adriana, Wirtz Stefan, Zundler Sebastian, Neurath Markus F
Аннотация
BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. Blimp-1 is a transcriptional repressor that, by interacting with other transcription factors in lymphocytes, regulates their cellular fate.
OBJECTIVE: In this study, we focused on the role of Blimp-1 in T cells in lung cancer.
METHODS: Here, we analyzed, in a murine model of NSCLC, the role of Blimp-1 in T cells after targeting Blimp-1 in T cells expressing lymphocyte-specific-protein tyrosine kinase (Lck), a kinase crucial for T-cell receptor signaling.
RESULTS: We found that mice lacking Blimp1 expression in T cells have reduced lung tumor load, suppressed lung Foxp3+Treg cells in the lung and draining lymph nodes, and induced T-bet+CD4+T effector cells producing IFN-gamma and interleukin-2. Furthermore, RNA sequencing of spleen CD4+T cells showed an induction of Th1 markers, including TNF, IL-2 and interferon type I-related genes, but also PD1. RNA sequencing of spleen CD8+T cells showed induced Tc1 markers, including IL12rb1, CD44, granzyme M and eomesodermin, in the absence of Blimp1. Finally, in the lung of mice with Blimp1 deficiency in T cells, we found an upregulation of CD8+T cells with increased release of cytotoxic mediators able to induce lung tumor cell death.
CONCLUSIONS: These data indicate that the tumor microenvironment induces Blimp-1 in immunosuppressive Treg and T effector cells, thereby limiting the therapeutic efficacy of anti-tumor immune responses. Targeting of Blimp-1 in T cells emerges as a novel concept to suppress immune evasion in lung cancer by regulating CD4+, CD8+and Treg function in the lung.
OBJECTIVE: In this study, we focused on the role of Blimp-1 in T cells in lung cancer.
METHODS: Here, we analyzed, in a murine model of NSCLC, the role of Blimp-1 in T cells after targeting Blimp-1 in T cells expressing lymphocyte-specific-protein tyrosine kinase (Lck), a kinase crucial for T-cell receptor signaling.
RESULTS: We found that mice lacking Blimp1 expression in T cells have reduced lung tumor load, suppressed lung Foxp3+Treg cells in the lung and draining lymph nodes, and induced T-bet+CD4+T effector cells producing IFN-gamma and interleukin-2. Furthermore, RNA sequencing of spleen CD4+T cells showed an induction of Th1 markers, including TNF, IL-2 and interferon type I-related genes, but also PD1. RNA sequencing of spleen CD8+T cells showed induced Tc1 markers, including IL12rb1, CD44, granzyme M and eomesodermin, in the absence of Blimp1. Finally, in the lung of mice with Blimp1 deficiency in T cells, we found an upregulation of CD8+T cells with increased release of cytotoxic mediators able to induce lung tumor cell death.
CONCLUSIONS: These data indicate that the tumor microenvironment induces Blimp-1 in immunosuppressive Treg and T effector cells, thereby limiting the therapeutic efficacy of anti-tumor immune responses. Targeting of Blimp-1 in T cells emerges as a novel concept to suppress immune evasion in lung cancer by regulating CD4+, CD8+and Treg function in the lung.