A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity

Meiser, Philippa; Knolle, Moritz A.; Hirschberger, Anna; de Almeida, Gustavo P.; Bayerl, Felix; Lacher, Sebastian; Pedde, Anna-Marie; Flommersfeld, Sophie; Hönninger, Julian; Stark, Leonhard; Stögbauer, Fabian; Anton, Martina; Wirth, Markus; Wohlleber, Dirk; Steiger, Katja; Buchholz, Veit R.; Wollenberg, Barbara; Zielinski, Christina E.; Braren, Rickmer; Rueckert, Daniel; Knolle, Percy A.; Kaissis, Georgios; Böttcher, Jan P.

doi:10.1016/j.ccell.2023.06.008

Cited by 40 publications

(28 citation statements)

References 76 publications

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“…Of note, no difference in proximity between pDCs or mature DCs and CD8 + T cells was found according to the response to immunotherapy. This supports the idea of a privileged interaction between cytotoxic lymphocytes and cDC1 to orchestrate the anti-tumor response in immunotherapy-treated patients as it was recently shown in melanoma mouse models by Meiser et al and Magen et al (32,49). Antoranz et al recently demonstrated that the phenotype and function of CD8 + T cells varied according to their localization, closer to the stroma-tumor interface or to the center of the melanoma tissue (50).…”

Section: E-f) Spatial Organization Between Cdc1 and Cd8 + T Cells Is ...supporting

confidence: 86%

“…Together, these results suggest that the structure of the CD8 + T cell network, rather than its density, is required for the efficacy of immunotherapy. Given that the DC composition in the TME influences CD8 + T cell infiltration and activation (31,32), we then analyzed the correlation and spatial organization between CD8 + T cells and DC subsets. The correlation between CD8 + T cell density and mature DCs was greater than that with other DC subsets (Fig.…”

Section: E-f) Spatial Organization Between Cdc1 and Cd8 + T Cells Is ...mentioning

confidence: 99%

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Spatial architecture of CD8⁺T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

Gobbini,

Hubert,

Doffin

et al. 2024

Preprint

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BackgroundDendritic cells (DCs) are promising targets for cancer immunotherapies owing to their central role in the initiation and the control of immune responses. Their functions encompass a wide range of mechanisms mediated by different DC subsets. Several studies have identified human tumor- associated DC (TA-DC) populations through limited marker-based technologies, such as immunostaining or flow cytometry. However, tumor infiltration, spatial organization and specific functions in response to immunotherapy of each DC subset remain to be defined.MethodsHere, we implemented a multiplexed immunofluorescence analysis pipeline coupled with bio-informatic analyses to decipher the tumor DC landscape and its spatial organization within melanoma patients’ lesions, and its association with patients’ response to immune checkpoint inhibitors (ICI). For this aim, we analyze a cohort of 41 advanced melanoma patients treated with anti- PD1 alone or associated with anti-CTLA4. Distance and cell network analyses were performed to gain further insight into the spatial organization of tumor-associated DCs. A Digital Spatial Profiling analysis further characterized ecosystem of tumor-infiltrating DCs.ResultsPlasmacytoid DCs (pDCs) were the most abundant DC population, followed by conventional cDC1 and mature DCs, present in equal proportions. In contrast to CD8+T cell frequency, and despite varying densities, all DC subsets were associated with a favorable response to ICI. Distance and cell network analyses demonstrated that tumor-infiltrating DCs were largely organized in dense areas with high homotypic connections, except for cDC1 that exhibited a more scattered distribution. We identified four patterns of ecosystems with distinct preferential interactions between DC subsets. Significantly, the proximity and interactions between CD8+T cells and cDC1 were positively associated with patients’ response to ICI.ConclusionsOur study unravels the complex spatial organization of DC subsets and their interactions in melanoma patient lesions, shedding light on their pivotal role in shaping the response to ICI. Our discoveries regarding the spatial arrangement of cDC1, especially with CD8+ T cells, provide valuable clues for improving immunotherapeutic strategies in melanoma patients.What is already known on this topicDendritic cells (DCs) are promising targets for cancer immunotherapies owing to their central role in the initiation and the control of immune responses. Although conventional type 1 dendritic cells (cDC1) were proposed to contribute to immunotherapy response, their precise functions and interactions with other immune populations in human cancers are largely unknown.What this study addsThis study provides a precise characterization of the spatial distribution and organization of tumor- infiltrating DCs in a large cohort of advanced melanoma patients, and in correlation with response to immunotherapy. While DCs are organized in dense areas with high homotypic connections, cDC1 exhibit a more scattered distribution and form heterotypic aggregates with other DC subsets. More importantly, a close connection between cDC1 and CD8 T cell is uniquely correlated with the patients’ response to immunotherapy.How this study might affect research, practice or policyThis study improves our understanding of CD8-DC spatial organization within the tumor microenvironment and will have a broad spectrum of implications in the design of anti-tumor immune-activating compounds and the design of biomarkers of response to immunotherapy for melanoma patients.

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Section: E-f) Spatial Organization Between Cdc1 and Cd8 + T Cells Is ...supporting

confidence: 86%

Section: E-f) Spatial Organization Between Cdc1 and Cd8 + T Cells Is ...mentioning

confidence: 99%

Spatial architecture of CD8⁺T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

Gobbini,

Hubert,

Doffin

et al. 2024

Preprint

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“…Of note, this mechanism may act in parallel to PGE 2 -mediated inhibition of cDC1 (ref. 38 ), which can support TCF1 + TIL responses within the tumour microenvironment 39 .…”

Section: Discussionmentioning

confidence: 99%

PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells

Lacher,

Dörr,

de Almeida

et al. 2024

Nature

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Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1–4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5–9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2–EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.

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“…This is in line with the findings that cDC1 are a key cross-presenting cell for antitumor CD8 + T cells and express T-cell–attracting chemokines ( 12 ). Outcomes for patients with HNSCC treated with standard-of-care therapies correlate with cDC1 infiltration ( 13 ), and furthermore, preclinical HNSCC models show the importance of cDC1 for aPD1 response ( 14 ). However, whether cDC1 infiltration correlates with ICB response in human patients with HNSCC has not yet been defined.…”

Section: Introductionmentioning

confidence: 99%

Targeting Dendritic Cell Dysfunction to Circumvent Anti-PD1 Resistance in Head and Neck Cancer

Saito,

Kono,

Nguyen

et al. 2024

Clinical Cancer Research

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Purpose: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed but further insights into the mechanisms underlying resistance and approaches to improve responses are needed. Experimental Design: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-Seq data to explore the mechanism of aPD1 resistance. Tumors and tumor draining lymph nodes (DLN) from MOC models were analyzed for antigen specific priming. CCL5 expression was enforced in an aPD1 resistant model. Results: An aPD1 resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1 resistant tumors compared to sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1 resistant model, intra-tumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1 resistant model enhanced cDC1 tumor infiltration, restored antigen specific responses, and recovered sensitivity to aPD1 treatment. Conclusions: These data highlight the contribution of tumor infiltrating cDC1s in HNSCC aPD1 response, and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in HNSCC patients.

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A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity

Cited by 40 publications

References 76 publications

Spatial architecture of CD8⁺T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

Spatial architecture of CD8⁺T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells

Targeting Dendritic Cell Dysfunction to Circumvent Anti-PD1 Resistance in Head and Neck Cancer

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A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity

Cited by 40 publications

References 76 publications

Spatial architecture of CD8+T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

Spatial architecture of CD8+T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells

Targeting Dendritic Cell Dysfunction to Circumvent Anti-PD1 Resistance in Head and Neck Cancer

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Product

Resources

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Spatial architecture of CD8⁺T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma

Spatial architecture of CD8⁺T cells and DC subsets is critical for the response to immune checkpoint inhibitors in melanoma