Author Correction: T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control

Steele, Maria M.; Jaiswal, Arvind Kumar; Delclaux, Ines; Dryg, Ian D.; Murugan, Dhaarini; Femel, Julia; Son, Sunny; Bois, Haley du; Hill, Cameron; Leachman, Sancy A.; Chang, Young Hwan; Coussens, Lisa M.; Anandasabapathy, Niroshana; Lund, Amanda W.

doi:10.1038/s41590-023-01491-4

Cited by 6 publications

(2 citation statements)

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“…Intratumoral vessels in well infiltrated tumors were larger with increased lumen area ( Supplementary Figures 6A, B ), indicating that a normalized, activated, and patent intratumoral vasculature may support T cell infiltration. We recently reported that when we looked at the presence of peritumoral lymphatic vessels in these same ROIs we observed a significant decrease in overall PDPN + vessel density that was driven by PDPN + LYVE-1 - inflamed lymphatic capillaries ( 38 ). Interestingly, both types of lymphatic vessels found peritumoral to infiltrated tumors exhibited a flattened morphology with increased eccentricity ( Supplementary Figures 6C, D ), perhaps indicating reduced mechanical stresses in the stroma (e.g.…”

Section: Resultsmentioning

confidence: 92%

Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma

Femel,

Hill,

Illa Bochaca

et al. 2024

Front. Immunol.

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IntroductionQuantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. MethodsWe established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. ResultsHere we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. DiscussionWe describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

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Section: Resultsmentioning

confidence: 92%

Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma

Femel,

Hill,

Illa Bochaca

et al. 2024

Front. Immunol.

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“…TGFb alters T cell migration using a variety of direct and indirect mechanisms. A study found that treatment with CXCL12 prompted CTLs to leave cutaneous tumors via lymphatic vessels (137), whereas suppression of CXCL12 expression in senescent tumor cells enhanced T cell infiltration in colonic tumors (138). A third study found that the metastatic properties of mesenchymal cancer cells decreased after CXCL12 was downregulated by TGFb (139).…”

Section: Tgfb Has Positive and Negative Effects On Tumor Progressionmentioning

confidence: 99%

The diverse effects of transforming growth factor-β and SMAD signaling pathways during the CTL response

Chandiran

Cauley

2023

Front. Immunol.

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Cytotoxic T lymphocytes (CTLs) play an important role in defense against infections with intracellular pathogens and anti-tumor immunity. Efficient migration is required to locate and destroy infected cells in different regions of the body. CTLs accomplish this task by differentiating into specialized subsets of effector and memory CD8 T cells that traffic to different tissues. Transforming growth factor-beta (TGFβ) belongs to a large family of growth factors that elicit diverse cellular responses via canonical and non-canonical signaling pathways. Canonical SMAD-dependent signaling pathways are required to coordinate changes in homing receptor expression as CTLs traffic between different tissues. In this review, we discuss the various ways that TGFβ and SMAD-dependent signaling pathways shape the cellular immune response and transcriptional programming of newly activated CTLs. As protective immunity requires access to the circulation, emphasis is placed on cellular processes that are required for cell-migration through the vasculature.

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Combined blockade of CXCR4 and PD-1 enhances intratumoral dendritic cell activation and immune responses against HCC

Morita,

Shigeta,

Lei

et al. 2023

Preprint

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Immune checkpoint inhibitors (ICIs) have transformed systemic therapy for unresectable hepatocellular carcinoma (HCC). Nevertheless, their efficacy is limited to a small percentage of patients, leaving an opportunity for enhancement through synergistic combination therapies. We tested here the combined blockade of programmed death receptor 1 (PD-1) and CXCR4, a receptor for CXCL12 and a key mediator of immunosuppression in the tumor microenvironment in orthotopic grafted and autochthonous models of HCC. We evaluated tumor growth and survival outcomes and examined the underlying mechanisms using immunofluorescence, flow cytometry, RNA-sequencing, and transgenic mice experiments. Combined anti-CXCR4/PD-1 therapy had a robust impact on tumor growth and significantly prolonged survival in all murine preclinical models. The combination treatment successfully reprogrammed antigen-presenting cells, revealing the role of conventional type 1 dendritic cells (cDC1s) in the tumor microenvironment. Moreover, DC reprogramming enhanced anti-cancer immunity by facilitating CD8 T-cell accumulation and activation in the HCC tissue. The effectiveness of the anti-CXCR4 antibody/ICI combination treatment was compromised entirely inBatf3-KO mice deficient in cDC1 cells. Thus, combined ICI therapy with an anti-CXCR4 antibody has the potential to augment the anti-cancer effects and improve survival outcomes in HCC via reprogramming intra-tumoral cDC1 cells.

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Author Correction: T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control

Cited by 6 publications

References 0 publications

Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma

Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma

The diverse effects of transforming growth factor-β and SMAD signaling pathways during the CTL response

Combined blockade of CXCR4 and PD-1 enhances intratumoral dendritic cell activation and immune responses against HCC

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