'Trained immunity: consequences for lymphoid malignancies

Stevens, Wendy B C; Netea, Mihai G.; Kater, Arnon P.; Velden, Walter J.F.M. van der

doi:10.3324/haematol.2016.149252

Cited by 25 publications

(22 citation statements)

References 88 publications

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“…Trained myeloid cells demonstrate elevated responses to subsequent challenge by unrelated antigens or pathogens, and the effect is long-lasting since transcriptional changes are induced by BCG in hematopoietic stem cells and myeloid progenitor cells 11 . These same trained immunity changes elicited by BCG may underly the immunotherapeutic effects of BCG in cancer prevention [65][66][67][68] . Therefore, another goal of this study was to evaluate whether or not the salutary effects of BCG in bladder cancer therapy are mediated through a trained immunity mechanism, and how overexpression of a STING agonist may modulate BCG-mediated trained immunity.…”

Section: Discussionmentioning

confidence: 88%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

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BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood. We developed a recombinant BCG (rBCG) that releases the STING agonist, c-di-AMP. Compared with BCG, rBCG demonstrated superior antitumor efficacy in models of NMIBC, more potent pro-inflammatory cytokine responses, greater myeloid cell reprogramming (M1 shift) and enhanced epigenetic and metabolomic changes favoring antitumor immunity. These findings are signatures of trained immunity and reveal that STING pathway activation is a proximal trigger in trained immunity remodeling. Trained immunity may be a central mechanism for both BCG and rBCG antitumor activity in NMIBC. INTRODUCTION:Bacillus Calmette-Guérin (BCG)--the only FDA-approved bacterial agent for cancer immunotherapy--has been in use for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC) as a first-line therapy since the late 1970s. More than one-third of patient's with NMIBC will experience tumor recurrence after receiving BCG, and these patients have limited options other than removal of the bladder and creation of a urinary diversion -a major life-altering event. Thus, there is a significant unmet need for improved versions of BCG that provide superior response rates and prevent disease progression 1 . At the current time intravesical options for bladder preserving therapy remain limited.Following bladder instillation, BCG induces a local inflammatory response accompanied by infiltration of granulocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and CD4 + and CD8 + T cells, accompanied by release of pro-inflammatory cytokines including IL-6, TNF-a, and IFN-g 2-7 . However, the specific immune mechanisms leading to BCG-mediated tumor eradication as well as BCG-resistance are not well-understood. BCG has been found to impart potent heterologous protection against non-related viral and bacterial infections; it elicits this protection via an innate immune memory mechanism known as trained immunity 8-11 . Trained immunity is characterized by metabolic, epigenetic and transcriptional reprogramming of both myeloid and lymphoid lineages 12-15 but it has not been extensively studied as an antitumor mechanism during BCG immunotherapy for NMIBC.Recent studies have implicated the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector, stimulator of interferon genes (STING), in a key immune response pathway known as the cytosolic surveillance pathway (CSP), which responds to DNA and cyclic dinucleotides aberrantly present in the cytosol [16][17][18][19] . Activated cGAS catalyzes the formation of 2′3′-cGAMP, a cyclic dinucleotide (CDN) that is a potent STING agonist.Activation of STING leads to stimulation of Type I interferon and NF-κB-mediated immune responses, including elevated dendritic cell priming and T-effector (Teff) cell recruitment 20-23 . 4Small molecule STING agonists elicit potent pro-inflammatory responses, and correspondingly have shown signific...

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Section: Discussionmentioning

confidence: 88%

WITHDRAWN: Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Singh

Praharaj

Lombardo

et al. 2020

Preprint

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“…The influence of timing of vaccine administration on nonspecific immunological effects of vaccines has not been investigated so far. Knowledge about possible oscillations in induction of BCG-induced trained immunity in vivo would be of great importance for assessing (nonspecific) vaccine efficacy, as well as for potential implications of BCG vaccination as immune modulator (12,33,34). Therefore, we investigated the effect of timing of BCG administration on the induction of trained immunity, in order to assess whether the time of day should be taken into account to maximize health benefits after BCG vaccination.…”

Section: Resultsmentioning

confidence: 99%

Circadian rhythm influences induction of trained immunity by BCG vaccination

Bree¹,

Mourits²,

Koeken³

et al. 2020

Journal of Clinical Investigation

105

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BACKGROUND. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. Eighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age-and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG. RESULTS. Compared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning-compared with evening-isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration.

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“…Remarkably, MBL exhibited activation of several functions related to pathogen recognition by innate immune cells (e.g., monocytes). Among them, phagocytosis and stimulation of PRRs such as TLR, which triggers the overexpression of pro-inflammatory genes [31], were highlighted. Similarly, a role was noted for HMGB1, which can bind to PRR to mediate cytokine production [32].…”

Section: Discussionmentioning

confidence: 99%