scholarly journals Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy

2021 ◽  
Vol 12 ◽  
Author(s):  
Sukanya Raghavan ◽  
Nataliya Tovbis-Shifrin ◽  
Christina Kochel ◽  
Anandi Sawant ◽  
Marielle Mello ◽  
...  

Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFNγ). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFNγ, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.

MicroRNA ◽  
2015 ◽  
Vol 4 (2) ◽  
pp. 117-122 ◽  
Author(s):  
Nato Teteloshvili ◽  
Katarzyna Smigielska-Czepiel ◽  
Bart-Jan Kroesen ◽  
Elisabeth Brouwer ◽  
Joost Kluiver ◽  
...  

AIDS ◽  
2013 ◽  
Vol 27 (13) ◽  
pp. 2101-2110 ◽  
Author(s):  
Judith J. Lok ◽  
Peter W. Hunt ◽  
Ann C. Collier ◽  
Constance A. Benson ◽  
Mallory D. Witt ◽  
...  

2021 ◽  
Author(s):  
Ming Li ◽  
Xiaojiang Xu ◽  
Qing Xu ◽  
Xin Xu ◽  
M Andrea Azcarate-Peril ◽  
...  

Dietary methionine restriction has been reported to repress cancer growth and improve therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the intact immune system is unknown. Here we report that methionine restriction exacerbates cancer growth and influences the outcomes of anti-tumor immunotherapy through gut microbiota and immune suppression in immunocompetent settings. Methionine restriction reduces T cell activation, increases tumor growth, and impairs response to anti-tumor immunotherapy. Mechanistically, methionine restriction alters composition of gut microbiota and reduces microbial production of hydrogen sulfide. Fecal transplantation from methionine-restricted tumor-free animals is sufficient to repress T cell activation and enhance tumor growth in tumor-bearing recipient mice. Conversely, dietary supplementation of a hydrogen sulfide donor or methionine stimulates anti-tumor immunity and suppresses tumor progression. Our findings reveal a vital role of gut microbiota in mediating methionine restriction-induced suppression of anti-tumor immunity and suggest that any possible anti-cancer benefits of methionine restriction require careful considerations of both the microbiota and the immune system.


Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3818-3823 ◽  
Author(s):  
Luca Gattinoni ◽  
Anju Ranganathan ◽  
Deborah R. Surman ◽  
Douglas C. Palmer ◽  
Paul A. Antony ◽  
...  

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation.


2007 ◽  
Vol 149 (2) ◽  
pp. 311-316 ◽  
Author(s):  
K. Bratke ◽  
L. Krieghoff ◽  
M. Kuepper ◽  
W. Luttmann ◽  
J. C. Virchow

2010 ◽  
Author(s):  
Vivian L. Weiss ◽  
Timothy H. Lee ◽  
Todd D. Armstrong ◽  
Elizabeth M. Jaffee

2007 ◽  
Vol 75 (5) ◽  
pp. 2244-2252 ◽  
Author(s):  
Patricia Ngai ◽  
Sarah McCormick ◽  
Cherrie Small ◽  
Xizhong Zhang ◽  
Anna Zganiacz ◽  
...  

ABSTRACT Gamma interferon (IFN-γ) is a key cytokine in host defense against intracellular mycobacterial infection. It has been believed that both CD4 and CD8 T cells are the primary sources of IFN-γ. However, the relative contributions of CD4 and CD8 T-cell subsets to IFN-γ production and the relationship between CD4 and CD8 T-cell activation have not been examined. By using a model of pulmonary mycobacterial infection and various immunodetection assays, we found that CD4 T cells mounted a much stronger IFN-γ response than CD8 T cells at various times after mycobacterial infection, and this pronounced IFN-γ production by CD4 T cells was attributed to both greater numbers of antigen-specific CD4 T cells and a greater IFN-γ secretion capacity of these cells. By using major histocompatibility complex class II-deficient or CD4-deficient mice, we found that the lack of CD4 T cells did not negatively affect primary or secondary CD8 T-cell IFN-γ responses. The CD8 T cells activated in the absence of CD4 T cells were capable of immune protection against secondary mycobacterial challenge. Our results suggest that, whereas both CD4 and CD8 T cells are capable of IFN-γ production, the former represent a much greater cellular source of IFN-γ. Moreover, during mycobacterial infection, CD8 T-cell IFN-γ responses and activation are independent of CD4 T-cell activation.


Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1488
Author(s):  
Stefania Farcomeni ◽  
Sonia Moretti ◽  
Caterina Fimiani ◽  
Lucia Fontanelli Sulekova ◽  
Fenicia Vescio ◽  
...  

Background: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV. Objectives: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed. Materials and Methods: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT). Results: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-β, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed. Conclusions: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Youqian Wu ◽  
Chao Zhang ◽  
Xiaolan Liu ◽  
Zhengfu He ◽  
Bing Shan ◽  
...  

AbstractCancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.


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