IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.

Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential.

Lymphatic vessel transit seeds cytotoxic resident memory T cells in skin draining lymph nodes.

Lymphatic transport shapes the homeostatic immune repertoire of lymph nodes (LNs). LN-resident memory T cells (T) play an important role in site-specific immune memory, yet how LN T form de novo after viral infection remains unclear. Here, we tracked the anatomical distribution of antiviral CD8 T cells as they seeded skin and LN T using a model of vaccinia virus-induced skin infection.

Lymphatic vessels in the age of cancer immunotherapy.

Lymphatic transport maintains homeostatic health and is necessary for immune surveillance, and yet lymphatic growth is often associated with solid tumour development and dissemination. Although tumour-associated lymphatic remodelling and growth were initially presumed to simply expand a passive route for regional metastasis, emerging research puts lymphatic vessels and their active transport at the interface of metastasis, tumour-associated inflammation and systemic immune surveillance. Here, we discuss active mechanisms through which lymphatic vessels shape their transport function to influence peripheral tissue immunity and the current understanding of how tumour-associated lymphatic vessels may both augment and disrupt antitumour immune surveillance.

Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas.

T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies.

The tumor-draining lymph node as a reservoir for systemic immune surveillance.

Early in solid tumor development, antigens are presented in tumor-draining lymph nodes (tdLNs), a process that is necessary to set up immune surveillance. Recent evidence indicates that tdLNs fuel systemic tumor-specific T cell responses which may halt cancer progression and facilitate future responses to immunotherapy. These protective responses, however, are subject to progressive dysfunction exacerbated by lymph node (LN) metastasis.

Lymphatic vessel transit seeds precursors to cytotoxic resident memory T cells in skin draining lymph nodes.

Resident memory T cells (T) provide rapid, localized protection in peripheral tissues to pathogens and cancer. While T are also found in lymph nodes (LN), how they develop during primary infection and their functional significance remains largely unknown. Here, we track the anatomical distribution of anti-viral CD8 T cells as they simultaneously seed skin and LN T using a model of skin infection with restricted antigen distribution.

Lymph node metastasis: An immunological burden.

Lymph node metastasis in breast cancer depends in part on the acquisition of an IFN-dependent, MHC-II+ state that induces regulatory T cell expansion and local immune suppression (Lei et al. 2023. J.

Structural Vulnerabilities in DLBCL for Enhanced Treatment Strategies.

Diffuse large B-cell lymphoma (DLBCL) is a typically immune-suppressed lymphoma subtype with poor response to immune checkpoint blockade and chimeric antigen receptor T-cell therapy. Recent data demonstrated an association between an activated, myofibroblast-like tumor stroma with improved outcome. On the basis of these findings, Apollonio and colleagues explored the phenotypic, transcriptional, and functional state of fibroblastic reticular cells (FRC) in human and murine DLBCL.

Telehealth Utilization in High-Risk Pregnancies During COVID-19.

Purpose: To determine how telehealth has influenced outcomes in high-risk obstetrics patients during the Coronavirus disease 2019 (COVID-19) pandemic.

Methods: A retrospective chart review was conducted to identify patterns in both telehealth and in-person clinic visits among patients of a Maternal Fetal Medicine (MFM) department from the onset of the COVID-19 pandemic from March 2020 until October 2021. For the descriptive analysis, -values were calculated using Wilcoxon rank sum for continuous variables and chi-square or Fisher exact (where cell  < 5) for categorical variables.

Angiopoietin-2-Dependent Spatial Vascular Destabilization Promotes T-cell Exclusion and Limits Immunotherapy in Melanoma.

Unlabelled: T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core.

T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control.

Antigen-specific CD8 T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8 T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention.

CXCR6 promotes dermal CD8 T cell survival and transition to long-term tissue residence.

Tissue resident memory T cells (T) provide important protection against infection, and yet the interstitial signals necessary for their formation and persistence remain incompletely understood. Here we show that antigen-dependent induction of the chemokine receptor, CXCR6, is a conserved requirement for T formation in peripheral tissue after viral infection. CXCR6 was dispensable for the early accumulation of antigen-specific CD8 T cells in skin and did not restrain their exit.

Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations.

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 2nd - 4th, 2021, Italy).

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response.

Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment.

Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment.

Immune Potential Untapped: Leveraging the Lymphatic System for Cancer Immunotherapy.

Over the past decade, our understanding of the role of the lymphatic vasculature in tumor progression has evolved from it being a passive participant, as a first step along Halsted's path of sequential metastasis, to a potentially active regulator of antitumor immune surveillance. These new data, however, seemingly support paradoxical predictions for cancer immunotherapy; on one hand that enhanced lymphatic involvement augments antitumor immune surveillance and on the other, drives immune evasion and metastasis. The potential to leverage lymphatic biology for the benefit of clinical immunotherapy, therefore, requires a mechanistic understanding of how the lymphatic vasculature interacts with functional immune responses during disease progression and in the context of relevant immunotherapy regimes.

Lymph node metastasis fuels systemic disease.

The functional impact of lymph node (LN) metastasis on systemic tumor progression has been a controversial question for decades. In their recent paper published in Cell, Reticker-Flynn et al. demonstrate that sequential evasion of natural killer (NK) cell control and interferon (IFN)-dependent epigenetic adaptation enhances the probability of LN metastasis.

Targeting LRG1 boosts immunotherapy.

Vascular normalization therapy has the potential to facilitate drug delivery and lymphocyte infiltration in tumors. Yet, optimal targets and dosage regimens remain elusive. In this issue of Med, O'Connor et al.

Be Easy and Chill: Melanoma Cells Tell Lymph Node Fibroblasts to Relax.

Melanomas coopt tumor-draining lymph nodes to support metastatic potential and install immunosuppression. The specific mechanisms that mediate lymph node education, however, remain incompletely understood. In this issue, Rovera and colleagues describe the deactivation of contractile lymph node fibroblasts by dedifferentiated melanoma cells, leading to lymph node expansion and enhanced melanoma invasive potential.

Fluorescent tracking identifies key migratory dendritic cells in the lymph node after radiotherapy.

Radiation therapy generates extensive cancer cell death capable of promoting tumor-specific immunity. Within the tumor, conventional dendritic cells (cDCs) are known to carry tumor-associated antigens to the draining lymph node (TdLN) where they initiate T-cell priming. How radiation influences cDC migration is poorly understood.