Biology subjects

Ogurtsova, A.

Publications and source records attributed to Ogurtsova, A..

2 recordsLinked to original sources

bioRxiv2024

Spatial multi-omics reveal intratumoral humoral immunity niches associated with tertiary lymphoid structures in pancreatic cancer immunotherapy pathologic responders

Pancreatic adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. We generated a spatial multi-omics atlas encompassing 26 PDAC tumors from patients treated with combination immunotherapies. Using machine learning-enabled H&E image classification models and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within TLS niches spanning across distinct morphologies and immunotherapies. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation in pathological responders, confirmed with spatial proteomics and BCR profiling. Our study also identifies spatial features of pathologic immune responses, revealing TLS maturation colocalizing with IgG/IgA distribution and extracellular matrix remodeling. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/613714v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@d5e1a5org.highwire.dtl.DTLVardef@1d14012org.highwire.dtl.DTLVardef@c57c6corg.highwire.dtl.DTLVardef@16baa56_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIIntegrated multi-modal spatial profiling of human PDAC tumors from neoadjuvant immunotherapy clinical trials reveal diverse spatial niches enriched in TLS. C_LIO_LITLS maturity is influenced by tumor location and the cellular neighborhoods in which TLS immune cells are recruited. C_LIO_LIUnsupervised machine learning of genome-wide signatures on spatial transcriptomics data characterizes the TLS-enriched TME and associates TLS transcriptomes with survival outcomes in PDAC. C_LIO_LIInteractions of spatially variable gene expression patterns showed TLS maturation is coupled with immunoglobulin distribution and ECM remodeling in pathologic responders. C_LIO_LIIntratumoral plasma cell and immunoglobin gene expression spatial dynamics demonstrate trafficking of TLS-driven humoral immunity in the PDAC TME. C_LI SignificanceWe report a spatial multi-omics atlas of PDAC tumors from a series of immunotherapy neoadjuvant clinical trials. Intratumorally, pathologic responders exhibit mature TLS that propagate plasma cells into malignant niches. Our findings offer insights on the role of TLS-associated humoral immunity and stromal remodeling during immunotherapy treatment.

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↗