β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

Majchrzak, Kinga; Nelson, Michelle H.; Bowers, Jacob S.; Bailey, Stefanie R.; Wyatt, Megan; Wrangle, John; Rubinstein, Mark P.; Varela, Juan Carlos; Li, Zihai; Himes, Richard A.; Chan, Sherine S.L.; Paulos, Chrystal M.

doi:10.1172/jci.insight.90547

Cited by 39 publications

(36 citation statements)

References 53 publications

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“…Thus, research efforts have focused on divorcing T cell expansion from differentiation [8,12,46]. Previous work by our group has shown that PI3Kδ inhibition with CAL-101 generates T cells with naïve/stem memory-like properties, thereby improving their therapeutic efficacy [35,36]. Herein, we report for the first time that ex vivo inhibition of PI3Kγ activity with IPI-549 endows murine T cells with similar therapeutic efficacy when infused into mice compared to those conditioned with PI3Kδ inhibitors.…”

Section: Discussionmentioning

confidence: 95%

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Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells

et al. 2020

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Adoptive T cell transfer therapy induces objective responses in patients with advanced malignancies. Despite these results, some individuals do not respond due to the generation of terminally differentiated T cells during the expansion protocol. As the gamma and delta catalytic subunits in the PI3K pathway are abundant in leukocytes and involved in cell activation, we posited that blocking both subunits ex vivo with the inhibitor IPI‐145 would prevent their differentiation, thereby increasing antitumor activity in vivo. However, IPI‐145 treatment generated a product with reduced antitumor activity. Instead, T cells inhibited of PI3Kγ (IPI‐549) or PI3Kδ (CAL‐101 or TGR‐1202) alone were more potent in vivo. While T cells coinhibited of PI3Kγ and PI3Kδ were less differentiated, they were functionally impaired, indicated by reduced production of effector cytokines after antigenic re‐encounter and decreased persistence in vivo. Human CAR T cells expanded with either a PI3Kγ or PI3Kδ inhibitor possessed a central memory phenotype compared to vehicle cohorts. We also found that PI3Kδ‐inhibited CARs lysed human tumors in vitro more effectively than PI3Kγ‐expanded or traditionally expanded CAR T cells. Our data imply that sole blockade of PI3Kγ or PI3Kδ generates T cells with remarkable antitumor properties, a discovery that has substantial clinical implications.

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Section: Discussionmentioning

confidence: 95%

“…In order to avoid in vivo toxicity, our group reported that CAL-101 can be used ex vivo to generate powerful antitumor T cells [35,36]. T cells treated with CAL-101 were less differentiated ex vivo and could persist with improved immunity in vivo.…”

Section: Introductionmentioning

confidence: 99%

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells

et al. 2020

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“…PI3K δ D910A mice show a reduced CD8 + T‐cell response to pathogenic Listeria monocytogenes infection, but improved bacterial clearance due to an enhancement of the innate immune response . Under specific circumstances, however, the attenuated phenotype of PI3K δ ‐deficient CD8 + T cells paradoxically results in an overall improvement of the desired immune response – in vitro treatment of T cells with inhibitors of the PI3K/Akt pathway has been shown to improve in vivo persistence and anti‐tumour efficacy when transfused into tumour‐bearing mice, by favouring a central‐memory phenotype over terminal differentiation as effectors …”

Section: Pi3k In the Immune Systemmentioning

confidence: 99%

“…57 Under specific circumstances, however, the attenuated phenotype of PI3Kd-deficient CD8 + T cells paradoxically results in an overall improvement of the desired immune responsein vitro treatment of T cells with inhibitors of the PI3K/Akt pathway has been shown to improve in vivo persistence and anti-tumour efficacy when transfused into tumour-bearing mice, by favouring a central-memory phenotype over terminal differentiation as effectors. [58][59][60] A requirement for PI3Kd in Treg-mediated tumour immunosuppression…”

Section: Pi3k In the Immune Systemmentioning

confidence: 99%

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

Lim

Okkenhaug

2019

Immunology

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Summary Tumour infiltration by regulatory T (Treg) cells contributes to suppression of the anti‐tumour immune response, which limits the efficacy of immune‐mediated cancer therapies. The phosphoinositide 3‐kinase (PI3K) pathway has key roles in mediating the function of many immune cell subsets, including Treg cells. Treg function is context‐dependent and depends on input from different cell surface receptors, many of which can activate the PI3K pathway. In this review, we explore how PI3Kδ contributes to signalling through several major immune cell receptors, including the T‐cell receptor and co‐stimulatory receptors such as CD28 and ICOS, but is antagonized by the immune checkpoint receptors CTLA‐4 and PD‐1. Understanding how PI3Kδ inhibition affects Treg signalling events will help to inform how best to use PI3Kδ inhibitors in clinical cancer treatment.

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“…Although ICOS has an established role in primary TFH responses, it's role in maintaining CD4 memory is less clear. ICOS signaling has been shown to induce the expression of Tcf7 in Th17 memory cells that maintain the plasticity to differentiate following stimulation (Majchrzak et al, 2017). ICOS can also induce mTORC1 activation in both TFH effector and T follicular regulatory (TFR) effector cells, leading to further stabilization of the follicular T cell program (Xu et al, 2017;Yang et al, 2016;Zeng et al, 2016).…”

Section: Icos Signaling Maintains Tfh Memory Cell Identity and Contrimentioning

confidence: 99%

Protection of bona fide T follicular memory cells during tissue isolation reveals their persistence, plasticity and functional impact

Künzli

Schreiner

Pereboom

et al. 2019

Preprint

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Running title: TFH memory cell persistence, identity and function 2 SUMMARY T follicular helper (TFH) cells regulate antibody production. Following infection or vaccination, effector TFH cells give rise to long-lived memory TFH cells. The survival requirements, lineage flexibility and impact of TFH memory cells have not been fully elucidated. In this study we determined that TFH memory cells persist to at least 400 days after infection while T cells with a central memory phenotype are largely absent.Single cell RNA sequencing reveals that TFH memory cells express many genes associated with stemness and self-renewal; reconstruction of a developmental trajectory suggests that TFH memory cells occur earlier in pseudotime, giving rise to other Th cell subsets in a linear fashion. Surprisingly, TFH memory cells concurrently express a distinct metabolic signature similar to trained immune cells, including elevated expression of mTOR, HIF-1 and cAMP regulated genes. TFH memory cell survival is mediated by ICOS signaling which acts as an integrator of glycolytic and self-renewal programming. Inhibition of ICOS at late time points leads to a reduction in TFH memory cells concomitant with decreased splenic plasma cells and circulating antibody titers.These results highlight the metabolic heterogeneity underlying distinct CD4 memory T cell subsets, linking TFH memory cell survival to sustained humoral immunity. 3 HIGHLIGHTS• TFH memory cells are long-lived and transcriptionally distinct from T central memory cells • TFH memory cells are multipotent following recall• TFH memory cells can be maintained in the absence of but requires ICOS signaling and glycolysis• TFH memory cells support late phase antibody production by splenic plasma cells 8 et al., 2014). TCM and Th1 clusters (4-7) exhibited higher expression of IL-7r, S100a4, S100a6, Selplg and various integrins ( Figures 2B and 2D), while clusters 6 and 7 were enriched for genes strongly associated with Th1 differentiation including Cxcr6, Ccl5, Nkg7 and Id2 (Figures 2B and 2E). Among Th1 clusters, cluster 7 represented the subset highest in Selplg, Ly6c2 and Il7r, while cluster 6 expressed higher levels of Cxcr6 and Id2 and exhibited signatures of dysfunction and exhaustion ( Figures S2D-S2F) (Ciucci et al., 2019;Martinez et al., 2015). Cluster cell-type identities were further confirmed by scoring each cell for signature genes obtained from publicly available datasets and examining the distributions of these scores across clusters ( Figures 2F and S2C). TFH and Th1 signatures matched well with clusters 1-3 and 6-7 respectively, while clusters 4, 5 and 7 were enriched for the TCM precursor signature reported by Ciucci et. al. (Figure 2F) (Ciucci et al., 2019). Clusters 4 and 5 had the highest Ccr7 transcription, which negatively correlated with Cxcr5 across all cells ( Figure 2G). To facilitate visualization of the relationship between Ccr7 and Cxcr5, we plotted expression levels imputed using the Seurat R package ( Figure 2H) (Satija et al., 2015).Within TFH clusters...

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β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

Cited by 39 publications

References 53 publications

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

Protection of bona fide T follicular memory cells during tissue isolation reveals their persistence, plasticity and functional impact

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β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity

Cited by 39 publications

References 53 publications

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8+ T cells

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8+ T cells

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

Protection of bona fide T follicular memory cells during tissue isolation reveals their persistence, plasticity and functional impact

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Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells