Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma

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

doi:10.1038/s41591-023-02345-0

Cited by 137 publications

(60 citation statements)

References 72 publications

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“…These observations are consistent with additional studies that have shown the importance of DCs for effective PD-1-targeted therapy (44)(45)(46). Furthermore, our recent data in hepatocellular carcinoma show that in tumors that respond to PD-1 blockade, Tpex are in close proximity to CXCL13 + helper CD4 T cells and DCs enriched in maturation (e.g., high expression of B7 ligands) and immunoregulatory molecules [e.g., programmed death ligand 1 (PD-L1)], described as mregDCs (12). In addition, responder patients also presented a higher number of effector-like Tex in the tumor microenvironment, suggesting that Tpex interactions with CD4 helpers and mregDCs may promote effective Tex differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…CD8 T cell responses during chronic stimulation are sustained by T cell factor 1 (TCF-1) + PD-1 + CD8 T cells that function as stem-like progenitor cells [precursor of exhausted T cells (Tpex)] to exhausted TCF-1 neg PD-1 + CD8 T cells [exhausted T cells (Tex)] (1,(3)(4)(5)(6). First described in murine chronic infection with lymphocytic choriomeningitis virus (LCMV) (4,6), Tpex have also been identified in tumor models (7,8), patients with cancer (7,(9)(10)(11)(12), and in type 1 diabetes (13,14). TCF-1 + PD-1 + Tpex self-renew to preserve persistent T cell responses and are also responsible for the proliferative burst that generates effectorlike cells after PD-1 blockade therapy (4,(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

“…In mice chronically infected with LCMV, Tpex predominantly reside in the T cell zone of lymphoid organs and do not recirculate ( 15 ). In tumor lesions, TCF-1 + CD8 T cells are found in antigen-presenting cell (APC)–rich niches ( 9 , 12 ). In patients with liver cancer, we recently reported that intratumoral dendritic cell (DC)–helper CD4 T cell niches may promote effective differentiation of Tpex after PD-1 blockade therapy ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…In tumor lesions, TCF-1 + CD8 T cells are found in antigen-presenting cell (APC)–rich niches ( 9 , 12 ). In patients with liver cancer, we recently reported that intratumoral dendritic cell (DC)–helper CD4 T cell niches may promote effective differentiation of Tpex after PD-1 blockade therapy ( 12 ). In accordance with those findings, Prokhnevska et al.…”

Section: Introductionmentioning

confidence: 99%

“…We previously showed that expansion of PD-1 + CD8 T cells after PD-1–targeted therapy is CD28 dependent ( 17 ). Tpex express high levels of CD28 ( 6 ) and localize in close proximity to APCs that express B7 proteins (CD28 ligands, CD80, and CD86) ( 9 , 12 , 18 ). Here, we sought to address the effects of CD28 engagement on Tpex self-renewal and differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells

Humblin,

Korpas,

et al. 2023

Sci. Immunol.

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During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1–positive (PD-1 + ) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1 neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1 + CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells

Humblin,

Korpas,

et al. 2023

Sci. Immunol.

Self Cite

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Cell Identity and Spatial Distribution of PD‐1/PD‐L1 Blockade Responders

Li,

Liu,

Gui

et al. 2024

Advanced Science

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The programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) axis inhibits T cell activity, impairing anti‐tumor immunity. Blocking this axis with therapeutic antibodies is one of the most promising anti‐tumor immunotherapies. It has long been recognized that PD‐1/PD‐L1 blockade reinvigorates exhausted T (TEX) cells already present in the tumor microenvironment (TME). However, recent advancements in high‐throughput gene sequencing and bioinformatic tools have provided researchers with a more granular and dynamic insight into PD‐1/PD‐L1 blockade‐responding cells, extending beyond the TME and TEX populations. This review provides an update on the cell identity, spatial distribution, and treatment‐induced spatiotemporal dynamics of PD‐1/PD‐L1 blockade responders. It also provides a synopsis of preliminary reports of potential PD‐1/PD‐L1 blockade responders other than T cells to depict a panoramic picture. Important questions to answer in further studies and the translational and clinical potential of the evolving understandings are also discussed.

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Single‐Nucleus and Spatial Transcriptome Profiling Delineates the Multicellular Ecosystem in Hepatocellular Carcinoma After Hepatic Arterial Infusion Chemotherapy

Huang,

Du,

Lai

et al. 2024

Advanced Science

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Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment strategy for hepatocellular carcinoma (HCC), but a detailed understanding of the multicellular ecosystem after HAIC treatment is lacking. Here, we collected tumor samples from treatment‐naïve primary and post‐HAIC HCC, and integrated single‐nucleus RNA sequencing with spatial transcriptomics to characterize the tumor ecosystem in the post‐HAIC HCC. Increased fractions and enhanced cellular communication of CD4+ T, CD20+ B, and dendritic cell subtypes were identified in post‐HAIC tumors. Moreover, it is substantiated that HAIC promoted tertiary lymphoid structures (TLS) formation, and addressed the roles of TLSs as spatial niches of cellular communication. Specifically, intermediate exhausted CD8+ T cells expressing Granzyme‐K and PD‐1 (PD‐1+CD8+ Tex‐int) expanded following HAIC and exhibited a functionally antitumor phenotype. PD‐1+CD8+ Tex‐int accumulated in the TLS vicinity and disseminated throughout the tumor microenvironment, demonstrating potential as an effective biomarker for HAIC‐based treatment in HCC. This study provides valuable resources and biological insights in the cellular underpinnings of HAIC treatment.

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Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma

Cited by 137 publications

References 72 publications

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells

Cell Identity and Spatial Distribution of PD‐1/PD‐L1 Blockade Responders

Single‐Nucleus and Spatial Transcriptome Profiling Delineates the Multicellular Ecosystem in Hepatocellular Carcinoma After Hepatic Arterial Infusion Chemotherapy

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Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma

Cited by 137 publications

References 72 publications

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 + PD-1 + CD8 T cells

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 + PD-1 + CD8 T cells

Cell Identity and Spatial Distribution of PD‐1/PD‐L1 Blockade Responders

Single‐Nucleus and Spatial Transcriptome Profiling Delineates the Multicellular Ecosystem in Hepatocellular Carcinoma After Hepatic Arterial Infusion Chemotherapy

Contact Info

Product

Resources

About

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 ⁺ PD-1 ⁺ CD8 T cells