Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

Tonnerre, Pierre; Wolski, David; Subudhi, Sonu; Aljabban, Jihad; Hoogeveen, Ruben C.; Damasio, Marcos; Drescher, Hannah K.; Bartsch, Lea M.; Tully, Damien C.; Sen, Debattama R.; Bean, David J.; Brown, Joelle; Torres-Cornejo, Almudena; Robidoux, Maxwell; Kvistad, Daniel; Alatrakchi, Nadia; Cui, Ang; Lieb, David; Cheney, James A.; Gustafson, Jenna; Lewis‐Ximenez, Lia Laura; Massenet-Regad, Lucile; Eisenhaure, Thomas; Aneja, Jasneet; Haining, W. Nicholas; Chung, Raymond T.; Hacohen, Nir; Allen, Todd M.; Kim, Arthur Y.; Lauer, Georg M.

doi:10.1101/2021.04.03.437705

Cited by 12 publications

(18 citation statements)

References 56 publications

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“…Antiviral cures for chronic LCMV infection do not exist, necessitating these adoptive transfer approaches. However, companion studies from human HCV infection (Tonnerre et al 49 , and Sen et al 50 ) and other recent work 51 , using direct acting antiviral treatment cures chronic viral infection, are consistent with the findings in the LCMV system. It will be interesting in the future to combine immunological and/or epigenetic therapies with cure approaches to potentially enhance the quality and durability of persisting immune memory.…”

Section: Discussionsupporting

confidence: 72%

Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

et al. 2021

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Exhausted CD8 T cells (T EX ) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies like PD-1 blockade can re-invigorate T EX cells, but re-invigoration is not durable. A major unanswered question is whether T EX cells differentiate into functional durable memory T cells (T MEM ) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, T EX cells partially (re)acquire phenotypic and transcriptional features of T MEM cells. These “recovering” T EX cells originated from the T-cell factor (TCF-1 + ) T EX progenitor subset. Nevertheless, the recall capacity of these recovering-T EX cells remained compromised compared to T MEM cells. Chromatin-accessibility profiling revealed failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for T EX cell targeted immunotherapies.

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Section: Discussionsupporting

confidence: 72%

Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

et al. 2021

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“…However, after BCG, clinically unresponsive patients had significantly higher expression levels of the immune inhibitory marker genes PD1, KLRG1, HAVCR2, CTLA4 , and LAG3 amongst others ( Fig. 2F-G 16 ).…”

Section: Resultsmentioning

confidence: 98%

“…cancer or chronic viral infections, CD8 T-cells may enter a dysfunctional, exhausted state. In this state, the T-cells are characterized by sustained expression of inhibitory receptors such as PD-1, CTLA-4, and CD244 and loss of effector functions such as cytokine secretion and proliferation [16][17][18] . Due to the impaired immune functions of these exhausted T-cells, reversal of this state is of high therapeutic interest for improving the antitumor effects of T-cells 18 .…”

Section: Introductionmentioning

confidence: 99%

Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer

Strandgaard

Lindskrog

Nordentoft

et al. 2022

Preprint

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BackgroundThe functional status of immune cells within the tumor microenvironment and tumor characteristics may explain Bacillus Calmette-Guérin (BCG)-failure in high-risk non-muscle invasive bladder cancer (NMIBC).ObjectiveTo characterize molecular correlates of BCG-failure using a multiomics approach.Design, Setting, and ParticipantsBCG-treated NMIBC patients (n=156) were included. Metachronous tumors were analyzed using RNA-sequencing (n=170) and whole exome sequencing (n=198). Urine samples were analyzed for immune-oncology related proteins (n=190), and tumor-derived DNA (tdDNA; n=192).Outcome Measurement and Statistical AnalysisPrimary endpoint was BCG-failure. Cox regression, Wilcoxon Rank Sum test, t-test or Fisher’s exact test were used.Results and LimitationsBCG caused activation of the immune system regardless of clinical response; however, immune-inhibitory proteins were observed in the urine of BCG-unresponsive patients post-treatment (CD70, PD1, CD5). BCG-failure was associated with post-BCG T-cell exhaustion (p=0.0021). Pre-BCG tumors from patients with post-BCG T-cell exhaustion were characterized by high expression of cell division and immune-related genes. A high post-BCG exhaustion prediction score in pre-BCG tumors was associated with worse post-BCG high-grade recurrence free survival (HGRFS), reflecting BCG-failure (p=0.0084). Pre-BCG tumors of class 2a and 2b were likewise associated with worse post-BCG HGRFS(p=0.0023). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p=0.023) and mutations in MUC4 (p=0.0007). Finally, absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p=0.028). The retrospective design, lack of maintenance BCG, and partial overlap in analyses are limitations to the study.ConclusionsBCG failure may be caused by T-cell exhaustion. Tumor subtype and Pre-BCG tumor characteristics may identify patients at high risk of BCG-failure prior to treatment. Urinary measurements have the potential to be used as a real-time assessment of treatment response.Patient SummaryA dysfunctional immune response to BCG therapy may explain lack of response to the treatment.

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“…Whereas this latter population was lost after DAA therapy, the memory-like T cells persisted. These cells have acquired a molecular signature of exhaustion during long-term chronic HCV infection and prevent immune restoration [11,12].…”

Section: Introductionmentioning

confidence: 99%

Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol‐associated disease etiology

et al. 2021

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Defective T-cell functions play a role in the persistence of HCV infection. Activated T cells express CD137, which costimulates antivirus T-cell responses, and this activity is antagonized by soluble CD137 (sCD137). Here, we show that in sera of 81 patients with chronic HCV, sCD137 levels did not correlate with measures of viral infection, and did not decline after virus eradication using direct-acting antivirals. Thus, serum sCD137 was similar in patients infected with HCV and in uninfected controls. Of note, in HCV patients with liver cirrhosis and patients with mostly alcohol-associated liver cirrhosis, sCD137 was increased. A negative association of sCD137 and albumin existed in both cohorts. sCD137 concentrations were similar in hepatic and portal vein blood excluding the liver as the origin of higher levels. Recombinant sCD137 reduced Th1 and Th2 but not Th17 cell polarization in vitro, and accordingly lowered IFN-γ, TNF, and IL-13 in cell media. Serum sCD137 is associated with inflammatory states, and positively correlated with serum TNF in cirrhotic HCV patients following virus eradication. Our study argues against a role of sCD137 in HCV infection and suggests a function of sCD137 in liver cirrhosis, which yet has to be defined.

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Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

Cited by 12 publications

References 56 publications

Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer

Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol‐associated disease etiology

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