Publications

Abstract

Metastasis to lymph nodes (LNs) is a common feature of disease progression in most solid organ malignancies. Consequently, LN biopsy and lymphadenectomy are common clinical practices, not only because of their diagnostic utility but also as a means of deterring further metastatic spread. LN metastases have the potential to seed additional tissues and can induce metastatic tolerance, a process by which tumor-specific immune tolerance in LNs promotes further disease progression. Nonetheless, phylogenetic studies have revealed that distant metastases are not necessarily derived from nodal metastases. Furthermore, immunotherapy efficacy is increasingly being attributed to initiation of systemic immune responses within LNs. We argue that lymphadenectomy and nodal irradiation should be approached with caution, particularly in patients receiving immunotherapy.

View details for DOI 10.1016/j.tcb.2023.04.001

View details for PubMedID 37149414

Abstract

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

View details for DOI 10.1016/j.cell.2022.04.019

View details for PubMedID 35525247

Abstract

Tumor immunology is undergoing a renaissance due to the recent profound clinical successes of tumor immunotherapy. These advances have coincided with an exponential growth in the development of -omics technologies. Armed with these technologies and their associated computational and modeling toolsets, systems biologists have turned their attention to tumor immunology in an effort to understand the precise nature and consequences of interactions between tumors and the immune system. Such interactions are inherently multivariate, spanning multiple time and size scales, cell types, and organ systems, rendering systems biology approaches particularly amenable to their interrogation. While in its infancy, the field of 'Cancer Systems Immunology' has already influenced our understanding of tumor immunology and immunotherapy. As the field matures, studies will move beyond descriptive characterizations toward functional investigations of the emergent behavior that govern tumor-immune responses. Thus, Cancer Systems Immunology holds incredible promise to advance our ability to fight this disease.

View details for DOI 10.7554/eLife.53839

View details for PubMedID 32657757

Abstract

Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection.

View details for DOI 10.1016/j.cell.2016.12.022

View details for PubMedID 28111070

Abstract

Metastasis is the leading cause of cancer-associated deaths. Although dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically relevant tumors. Recent studies have uncovered many molecular factors that contribute to the establishment of a protumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical associations with advanced malignancy and poor outcome, contributes to metastatic niche formation by binding to carbohydrates on metastatic cells. We show that galectin-3 is expressed early during tumorigenesis by both CD11b(+)Gr-1(+) and CD11b(+)Ly-6C(hi) leukocytes. Tumors mobilize these myeloid populations through secretion of soluble factors, including IL6. We find that metastatic cancer cells exhibit elevated presentation of the oncofetal galectin-3 carbohydrate ligand, the Thomsen-Friedenreich antigen, on their surfaces as a result of altered C2GnT2 and St6GalNAc4 glycosyltransferase activity that inhibits further glycosylation of this carbohydrate motif and promotes metastasis.Although clinical observations of elevated serum galectin-3 levels and altered glycosylation have been associated with malignancy, we identify novel roles for glycosyltransferases in promoting adhesion to galectins in the metastatic niche. This identification of a cytokine-leukocyte-glycosylation axis in metastasis provides mechanistic explanations for clinical associations between malignancy and aberrant glycosylation.

View details for DOI 10.1158/2159-8290.CD-13-0760

View details for Web of Science ID 000349393600025

View details for PubMedID 25421439

View details for PubMedCentralID PMC4367955

Abstract

Extracellular matrix interactions have essential roles in normal physiology and many pathological processes. Although the importance of extracellular matrix interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Here we report a novel-screening platform capable of measuring phenotypic responses to combinations of extracellular matrix molecules. Using a genetic mouse model of lung adenocarcinoma, we measure the extracellular matrix-dependent adhesion of tumour-derived cells. Hierarchical clustering of the adhesion profiles differentiates metastatic cell lines from primary tumour lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8 or laminin. We show that these molecules correlate with human disease and that their interactions are mediated in part by α3β1 integrin. Thus, our platform allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified extracellular matrix and integrin interactions that could serve as therapeutic targets.

View details for DOI 10.1038/ncomms2128

View details for Web of Science ID 000313514100032

View details for PubMedID 23047680