Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Magen, Assaf; Hamon, Pauline; Fiaschi, Nathalie; Troncoso, Leanna; Humblin, Étienne; D’souza, Darwin; Dawson, Travis; Park, Matthew D.; Kim, Joel; Hamel, Steven; Buckup, Mark; Chang, Christie; Tabachnikova, Alexandra; Schwartz, Hara; Malissen, Nausicaa; Lavin, Yonit; Soares‐Schanoski, Alessandra; Giotti, Bruno; Hegde, Samarth; Mattiuz, Raphaël; Hennequin, Claire; Bérichel, Jessica Le; Zhao, Zhen; Ward, Stephen; Fiel, Isabel; Price, Colles; Fernandez, Nicolas; He, Jiang; Kou, Baijun; Dobosz, Michael; Li, Lianjie; Adler, Christina; Ni, Min; Wei, Yi; Wang, Wei; Gupta, Namita; Kundu, Kunal; Cygan, Kamil J.; Deering, Raquel P.; Tsankov, Alex; Kim‐Schulze, Seunghee; Gnjatic, Sacha; Kenigsberg, Ephraim; Schwartz, Myron; Marron, Thomas U.; Thurston, Gavin; Kamphorst, Alice O.; Mérad, Miriam

doi:10.1101/2022.06.22.497216

Cited by 9 publications

(11 citation statements)

References 84 publications

(144 reference statements)

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“…The involvement of Tfh cells in response to anti-PD-1 mAb in lymph nodes represents an intriguing parallel to some recent observations made at the tumor site ( Cohen et al, 2022 ; Gu-Trantien et al, 2013 ; Magen et al, 2022 , Preprint ; Niogret et al, 2021 ; Sánchez-Alonso et al, 2020 ). Indeed, the presence of intratumor CD4 + T cells expressing Tfh markers (including CXCL13 and PD-1 high ) in multiple types of carcinomas is associated with better cancer outcomes ( Gu-Trantien et al, 2013 ; Niogret et al, 2021 ) and favorable responses to anti-PD-1 therapy ( Magen et al, 2022 , Preprint ). Of note, these cells were found to interact with intratumoral DCs ( Cohen et al, 2022 ; Magen et al, 2022 , Preprint ).…”

Section: Discussionsupporting

confidence: 64%

“…Indeed, the presence of intratumor CD4 + T cells expressing Tfh markers (including CXCL13 and PD-1 high ) in multiple types of carcinomas is associated with better cancer outcomes ( Gu-Trantien et al, 2013 ; Niogret et al, 2021 ) and favorable responses to anti-PD-1 therapy ( Magen et al, 2022 , Preprint ). Of note, these cells were found to interact with intratumoral DCs ( Cohen et al, 2022 ; Magen et al, 2022 , Preprint ). In addition, adoptive transfer of in vitro–generated Tfh-like cells can enhance antitumor activity in mouse models ( Cohen et al, 2022 ; Niogret et al, 2021 ), in particular, through the production of IL-21 ( Niogret et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes

Ruggiu,

Guérin,

Corre

et al. 2024

Journal of Experimental Medicine

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Anti-PD-1 therapy targets intratumoral CD8+ T cells to promote clinical responses in cancer patients. Recent evidence suggests an additional activity in the periphery, but the underlying mechanism is unclear. Here, we show that anti-PD-1 mAb enhances CD8+ T cell responses in tumor-draining lymph nodes by stimulating cytokine production in follicular helper T cells (Tfh). In two different models, anti-PD-1 mAb increased the activation and proliferation of tumor-specific T cells in lymph nodes. Surprisingly, anti-PD-1 mAb did not primarily target CD8+ T cells but instead stimulated IL-4 production by Tfh cells, the major population bound by anti-PD-1 mAb. Blocking IL-4 or inhibiting the Tfh master transcription factor BCL6 abrogated anti-PD-1 mAb activity in lymph nodes while injection of IL-4 complexes was sufficient to recapitulate anti-PD-1 mAb activity. A similar mechanism was observed in a vaccine model. Finally, nivolumab also boosted human Tfh cells in humanized mice. We propose that Tfh cells and IL-4 play a key role in the peripheral activity of anti-PD-1 mAb.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes

Ruggiu,

Guérin,

Corre

et al. 2024

Journal of Experimental Medicine

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“…Tfh-like cells in non-lymphoid tissues support humoral and cell-mediated responses by recruiting B cells and supplying IL21 ( 21, 23, 26, 27, 30, 31, 42, 61 ). Indeed, a recent study showed that Tfh-like cells recruit precursor CD8 T cells and DCs using the oxysterol metabolite 7α,25-HC, which may support a niche for differentiation of effector cells in hepatocellular carcinomas ( 62 ). Moreover, our meta-analysis on the TCGA cohort of HGSOC and several cohorts of ICB-treated showed the improved clinical response associated with these lymphoid aggregates formed by Tfh-like cells.…”

Section: Discussionmentioning

confidence: 99%

Predicting developmental relationships of tumor resident and circulating T cells in ovarian cancer

Carneiro

Barèche

Zhao

et al. 2023

Preprint

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Characterizing T cell populations and understanding their developmental relationships may help design more effective cancer immunotherapies. We coupled single-cell transcriptomics and T cell receptor (TCR) αβ profiling of intratumoral and peripheral T cells in ovarian cancer patients to identify transcriptional programs and infer their relationship by trajectory and TCR overlap analyses. We proposed a model of differentiation pathway from an intermediate GZMH-expressing CD8 T cell subset found in the blood and tumor that progressively reinforces the exhaustion and tissue residency programs from aCCL4-expressing cluster towardsXCL1- andCXCL13-expressing terminally exhausted cells. Inferred cell communication analysis suggests that interaction withCXCL13-expressing CD4 T cells, which we refer to as Tfh-like cells, sustains the effector function of this intermediate GZMH-expressing CD8 T cell subset. Moreover, our results suggest that Tfh-like cells attract cells expressingGPR183through the production of its ligand 7α,25 dihydroxycholesterol (7α,25-HC). Finally, we demonstrated thatGPR183is highly expressed in a subset of pre-effectorGZMK-expressing CD8 T cells and plasmacytoid dendritic cells. Collectively, our results suggest that Tfh-like cells expressing IL-21 help promote antitumor immunity against ovarian tumors by coordinating the action of immune cells responsive to 7α,25-HC.

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“…To specify an mregDC signature that is conserved across different non-lymphoid tissues, we performed our own independent analysis of mregDCs by collating publicly available scRNAseq data on human and murine cDCs 3,5,24,27,40,51,57 ( Fig. 1a ).…”

Section: Main Textmentioning

confidence: 99%

AXL limits the mobilization of cholesterol to regulate dendritic cell maturation and the immunogenic response to cancer

Belabed,

Park,

Blouin

et al. 2023

Preprint

Self Cite

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SummaryWe previously found that uptake of cellular debris prompts conventional dendritic cells (cDCs) to undergo maturation. This transformation results in DCs entering the molecular state termed ‘mregDC’. In this state, mregDCs dampen their ability to acquire new antigens, upregulate chemokine receptors to migrate to lymphoid organs, and upregulate MHC-I and -II, co-stimulatory, and -inhibitory molecules to promote the differentiation of antigen-specific T cells. Here, we show that cholesterol mobilization – through bothde novosynthesis and the acquisition of the metabolite during debris uptake – drives cDCs to mature into mregDCs. This cholesterol is used to assemble lipid nanodomains on the plasma membrane of mregDCs to support cell surface expression of maturation markers. This process is dependent on bothde novosynthesis and Niemann-Pick disease type C1 (NPC1), which shuttles cholesterol from the endolysosomal pathway. Specifically, NPC1 mediated the accumulation of IFN-ɣ receptor (IFNɣR) in cell surface lipid nanodomains, enabling optimal IFNɣR signaling required for IL-12 production and efficient T cell activation. Importantly, we also show that the receptor tyrosine kinase AXL constitutively dampens the cholesterol-dependent construction of lipid nanodomains on mregDCs; its deletion from cDCs enhance mregDC immunogenicity and yielded potent anti-tumor immunity in an experimental model of lung cancer. Altogether, our findings present novel insights into the mobilization of cholesterol for proper immune receptor signaling as a basis for cDC maturation and the novel role of AXL as a central regulator of this process that can be therapeutically targeted to leverage the immunostimulatory features of mregDCs.

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Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Cited by 9 publications

References 84 publications

Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes

Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes

Predicting developmental relationships of tumor resident and circulating T cells in ovarian cancer

AXL limits the mobilization of cholesterol to regulate dendritic cell maturation and the immunogenic response to cancer

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