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Lymph node metastasis: An immunological burden

Lund, Amanda W
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. Exp. Med.https://doi.org/10.1084/jem.20221847).
PMID: 37417951
ISSN: 1540-9538
CID: 5536922

Structural vulnerabilities in DLBCL for enhanced treatment strategies

Cristaldi, Vanessa; Lund, Amanda W
Diffuse large B-cell lymphoma (DLBCL) is a typically immune suppressed lymphoma subtype with poor response to immune checkpoint blockade and CAR T cell therapy. Recent data demonstrated an association between an activated, myofibroblast-like tumor stroma with improved outcome. Based on these findings, Apollonio and colleagues explored the phenotypic, transcriptional, and functional state of fibroblastic reticular cells (FRC) in human and murine DLBCL. This study reveals that DLBCL cells trigger the activation and remodeling of FRCs, leading to a chronic inflammatory state that supports malignant B cell survival. Transcriptional reprogramming of the FRCs may inhibit CD8+ T cell migration and function through changes in homing chemokines, adhesion molecules, and antigen presentation machinery, which together limit the anti-DLBCL immune response. High-dimensional imaging mass cytometry revealed heterogeneous CD8+ T Cell and FRC neighborhoods that associated with different clinical outcomes and ex vivo modeling of the microenvironment indicated an opportunity to target the FRC network for improved T cell motility, infiltration, and effector function. This research broadens our understanding of the complex interactions between the lymph node microarchitecture and anti-tumor immune surveillance, defines structural vulnerabilities in DLBCL, and thereby offers opportunities for combined therapeutic approaches.
PMID: 37404051
ISSN: 1538-7445
CID: 5539142

Angiopoietin-2-dependent spatial vascular destabilization promotes T-cell exclusion and limits immunotherapy in melanoma

Park, Ha-Ram; Shiva, Anahita; Cummings, Portia; Kim, Seoyeon; Kim, Sungsoo; Lee, Eunhyeong; Leong, Alessandra; Chowdhury, Subrata; Shawber, Carrie; Carvajal, Richard; Thurston, Gavin; An, Joon Yong; Lund, Amanda W; Yang, Hee Won; Kim, Minah
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. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacological and genetic blockade of ANGPT2 promoted CD8+ T cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy responsive mouse melanomas, but it also rendered non-responsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.
PMID: 37093870
ISSN: 1538-7445
CID: 5465042

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

Steele, Maria M; Jaiswal, Abhinav; Delclaux, Ines; Dryg, Ian D; Murugan, Dhaarini; Femel, Julia; Son, Sunny; du Bois, Haley; Hill, Cameron; Leachman, Sancy A; Chang, Young H; Coussens, Lisa M; Anandasabapathy, Niroshana; Lund, Amanda W
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. A diverse repertoire of functional tumor-specific CD8+ T cells, therefore, exit the tumor, which limits the pool of CD8+ T cells available to exert tumor control. CXCR4 inhibition or loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. These data indicate that strategies to limit T cell egress might be an approach to boost the quantity and quality of intratumoral T cells and thereby response to immunotherapy.
PMID: 36849745
ISSN: 1529-2916
CID: 5448422

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

Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H; Lund, Amanda W; Welling, Theodore H; Dolgalev, Igor; Tsirigos, Aristotelis; Simeone, Diane M
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. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
PMCID:9925748
PMID: 36781852
ISSN: 2041-1723
CID: 5427092

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

Blair, Tiffany C; Bambina, Shelly; Kramer, Gwen F; Dowdell, Alexa K; Alice, Alejandro F; Baird, Jason R; Lund, Amanda W; Piening, Brian D; Crittenden, Marka R; Gough, Michael J
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. Here, we show that immunological efficacy of radiation therapy is dependent on cDC migration in radioimmunogenic tumors. Using photoconvertible mice, we demonstrate that radiation impairs cDC migration to the TdLN in poorly radioimmunogenic tumors. Comparative transcriptional analysis revealed that cDCs in radioimmunogenic tumors express genes associated with activation of endogenous adjuvant signaling pathways when compared with poorly radioimmunogenic tumors. Moreover, an exogenous adjuvant combined with radiation increased the number of migrating cDCs in these poorly radioimmunogenic tumors. Taken together, our data demonstrate that cDC migration play a critical role in the response to radiation therapy.
PMCID:9058260
PMID: 35487695
ISSN: 2575-1077
CID: 5215662

Lymph node metastasis fuels systemic disease

Ventre, Katherine S; Karakousi, Triantafyllia; Lund, Amanda W
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. Further, they show that, once formed, LN metastases expand systemic peripheral tolerance and promote distant organ metastasis.
PMID: 35717536
ISSN: 2405-8025
CID: 5277942

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

Barkley, Dalia; Moncada, Reuben; Pour, Maayan; Liberman, Deborah A; Dryg, Ian; Werba, Gregor; Wang, Wei; Baron, Maayan; Rao, Anjali; Xia, Bo; França, Gustavo S; Weil, Alejandro; Delair, Deborah F; Hajdu, Cristina; Lund, Amanda W; Osman, Iman; Yanai, Itai
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. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis.
PMID: 35931863
ISSN: 1546-1718
CID: 5286422

Immune Potential Untapped: Leveraging the Lymphatic System for Cancer Immunotherapy

Lund, Amanda W
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. In this review, I dissect the promise and challenge of engaging the lymphatic system for therapy and suggest important avenues for future investigation and potential application.
PMID: 35895021
ISSN: 2326-6074
CID: 5276632

Niche topics and location, location, location, with Amanda Lund [Editorial]

Lund, Amanda W; Delgoffe, Greg M
PMID: 35587566
ISSN: 1365-2567
CID: 5284312