Biology subjects

Coyne, E. M.

Publications and source records attributed to Coyne, E. M..

3 recordsLinked to original sources

bioRxiv2024

Mapping the breast tumor microenvironment: proximity analysis reveals spatial relationships between macrophage subtypes and metastasis-initiating cancer cells

The development of metastasis, responsible for the majority of cancer-related fatalities, is the most dangerous aspect of breast cancer, the predominant malignancy affecting women. We previously identified specific cancer cell populations responsible for metastatic events which are cytokeratin-14 (CK14) and E-cadherin positive in luminal tumors, and E-cadherin and vimentin positive in triple-negative tumors. Since cancer cells evolve within a complex ecosystem comprised of immune cells and stromal cells, we sought to decipher the spatial interactions of these aggressive cancer cell populations within the tumor microenvironment (TME). We used imaging mass cytometry to detect 36 proteins in tumor microarrays containing paired primary and metastatic lesions from luminal or triple-negative breast cancers (TNBC), resulting in a dataset of 1,477,337 annotated cells. Focusing on metastasis-initiating cell populations, we observed close proximity to specific fibroblast and macrophage subtypes, a relationship maintained between primary and metastatic tumors. Notably, high CK14 in luminal cancer cells and high vimentin in TNBC cells correlated with close proximity to specific macrophage subtypes (CD163intCD206intPDL1intHLA-DR+ or PDL1highARG1high). Our in-depth spatial analysis elucidates that metastasis-initiating cancer cells exhibit with distinct cell populations within the TME, implicating the role of these cell-cell interactions in promoting metastasis.

cancer biology↗

bioRxiv2023

Preventing NK cell activation in the damaged liver induced by cabozantinib/PD-1 blockade increases survival in hepatocellular carcinoma models

Combining multikinase inhibitors with immune checkpoint blockade improves tumor control in hepatocellular carcinoma (HCC), but survival benefits remain inconsistent. To define this discordance, we integrated COSMIC-312 with orthotopic and autochthonous murine HCC models with or without liver fibrosis. In patients treated with cabozantinib plus atezolizumab, baseline liver function stratified overall survival but not progression-free survival, indicating uncoupling of tumor control from survival. In contrast, sorafenib outcomes tracked with both endpoints, supporting a treatment-specific effect rather than a purely prognostic effect of liver status. In murine HCC models, cabozantinib plus PD-1 blockade induced comparable tumor regression regardless of liver condition, but improved survival only in mice with preserved liver function, whereas fibrotic hosts developed hepatotoxicity. Immune profiling revealed compartment-specific remodeling, with enhanced cytotoxic T-cell programs in tumors but expansion of NK-lineage innate lymphocytes with ILC1-like features in fibrotic liver. Depletion of NK1.1-positive cells reduced liver injury and restored survival without compromising antitumor efficacy, whereas CD4-positive or CD8-positive T-cell depletion did not protect from hepatotoxicity. Transcriptomic, single-cell, adoptive-transfer, and human in vitro studies supported a model in which the fibrotic liver niche promotes NK-to-ILC1-like reprogramming, hepatocyte stress signaling, and TNF/TRAIL-associated epithelial injury. Consistently, cabozantinib and nivolumab showed liver-predominant remodeling of CD56-positive innate lymphocyte-enriched populations in human HCC samples, and ex vivo TGF-beta induced ILC1-like phenotypic changes in human NK cells. These findings identify liver fibrosis as a host determinant that can limit the survival benefit of multikinase inhibitor immunotherapy by promoting innate immune-mediated hepatotoxicity despite preserved tumor control in HCC. One Sentence SummaryLiver fibrosis limits the survival benefit of multikinase inhibitor immunotherapy in hepatocellular carcinoma by promoting innate immune-mediated hepatotoxicity despite preserved tumor control.

cancer biology↗

bioRxiv2023

Immune landscape of tertiary lymphoid structures in hepatocellular carcinoma (HCC) treated with neoadjuvant immune checkpoint blockade

Neoadjuvant immunotherapy is thought to produce long-term remissions through induction of antitumor immune responses before removal of the primary tumor. Tertiary lymphoid structures (TLS), germinal center-like structures that can arise within tumors, may contribute to the establishment of immunological memory in this setting, but understanding of their role remains limited. Here, we investigated the contribution of TLS to antitumor immunity in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy. We found that neoadjuvant immunotherapy induced the formation of TLS, which were associated with superior pathologic response, improved relapse free survival, and expansion of the intratumoral T and B cell repertoire. While TLS in viable tumor displayed a highly active mature morphology, in areas of tumor regression we identified an involuted TLS morphology, which was characterized by dispersion of the B cell follicle and persistence of a T cell zone enriched for ongoing antigen presentation and T cell-mature dendritic cell interactions. Involuted TLS showed increased expression of T cell memory markers and expansion of CD8+ cytotoxic and tissue resident memory clonotypes. Collectively, these data reveal the circumstances of TLS dissolution and suggest a functional role for late-stage TLS as sites of T cell memory formation after elimination of viable tumor. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/562104v2_fig0.gif" ALT="Figure 0"> View larger version (30K): org.highwire.dtl.DTLVardef@859572org.highwire.dtl.DTLVardef@169ed2org.highwire.dtl.DTLVardef@11510f0org.highwire.dtl.DTLVardef@b39a4_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LSTHighlightsC_LSTO_LIIn patients with hepatocellular carcinoma (HCC), tertiary lymphoid structures (TLS) are induced by neoadjuvant immunotherapy and are associated with favorable clinical outcomes. C_LIO_LITLS within the same tumor demonstrate extensive sharing of expanded granzyme K and granzyme B-expressing CD8+ T effector memory clonotypes, but the B cell repertoires of individual TLS are almost wholly distinct, consistent with independent germinal center reactions. C_LIO_LIWithin areas of viable tumor, mature TLS are characterized by high expression of CD21 and CD23, BCL6+ germinal center B cells, and close interactions between DCLAMP+ mature dendritic cells and CXCR5-CXCR3+ CD4 T peripheral helper cells within a T cell zone adjacent to the B cell follicle. C_LIO_LIWithin areas of tumor regression, an involuted TLS morphology is identified that is notable for dissolution of the B cell germinal center, retention of the T cell zone, and increased T cell memory. C_LI

immunology↗