Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA227088 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.
2014-08-05 | E-GEOD-52171 | biostudies-arrayexpress
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME.
2014-08-05 | GSE52171 | GEO
Project description:Tertiary lymphoid structures are immune cell aggregates linked with cancer outcomes, but their interactions with tumour cell aggregates are unclear. Using nasopharyngeal carcinoma as a model, we analyse single-cell transcriptomes of 343,829 cells from 77 biopsy and blood samples and spatially-resolved transcriptomes of 31,316 spots from 15 tumours to decipher their components and interactions with tumour cell aggregates. We identify essential cell populations in tertiary lymphoid structure, including CXCL13+ cancer-associated fibroblasts, stem-like CXCL13+CD8+ T cells, and B and T follicular helper cells. Our study shows that germinal centre reaction matures plasma cells. These plasma cells intersperse with tumour cell aggregates, promoting apoptosis of EBV-related malignant cells and enhancing immunotherapy response. CXCL13+ cancer-associated fibroblasts promote B cell adhesion and antibody production, activating CXCL13+CD8+ T cells that become exhausted in tumour cell aggregates. Tertiary lymphoid structure-related cell signatures correlate with prognosis and PD-1 blockade response, offering insights for therapeutic strategies in cancers.
2024-09-11 | GSE206245 | GEO
Project description:The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.
2022-11-02 | GSE198079 | GEO
Project description:The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.
2022-11-02 | GSE198069 | GEO
Project description:T lymphocytes can efficiently counteract the growth of tumors within the tumor microenvironment. Specialized immune-interacting fibroblasts, termed fibroblastic reticular cells (FRC) are responsible for the formation of specialized niches promoting immune cell activation in secondary lymphoid organs and originate from embryonic progenitors. FRCs have also been identified in tertiary lymphoid structures (TLS) in tumor tissues. However, the identity and differentiation of TLS-associated FRC subsets that promote intra-tumoral T cell activity have remained unexplored. Here, we employed single cell RNA-sequencing of fibroblasts and immune cells, sampled from subpleural margin, central margin and unaffected lung tissue in non small cell lung cancer (NSCLC), demonstrating the formation of specific tumor T cell environments (TTEs) underpinned by CCL19-expressing FRCs. We detected tumor-specific FRC subsets namely CCL19-expressing TRCs and perivascular reticular cells (PRCs) interacting with intratumoral T cells, and thus regulating FRC differentiation and T cell activation. Our results highlight a remarkable functionality of FRCs to efficiently determine protective antitumoral T cell responses in NSCLC.
2024-11-19 | E-MTAB-13710 | biostudies-arrayexpress
Project description:The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
2022-03-03 | GSE175540 | GEO
Project description:Immune responses against tumor cells depend on T lymphocyte attraction and activity within the tumor microenvironment. Specialized immune-interacting fibroblasts, commonly referred to as fibroblastic reticular cells (FRC), form specialized niches in secondary lymphoid organs, originate from embryonic progenitors and foster T cell activation. FRCs have also been detected in tertiary lymphoid structures (TLS) in tumors, differentiating from cancer associated fibroblasts. However, the identity and differentiation of niche-forming cells that foster intra-tumoral T cell activity have remained elusive. Here, we employed single cell RNA-sequencing of EYFP+ fibroblasts and GP33/34-Tetramer+CD8+ T cells from experimental murine lung cancer and cell fate-mapping analysis, which revealed the ability of FRC subsets in lung tumors to differentiate from progenitors situated in mural and adventitial sites. Ablation of FRC progenitors in Tumor T cell environments (TTEs) of murine lungs led to reduced anti-tumor T cell activity and loss of tumor control during experimental coronavirus vector-based immunotherapy. Collectively, our study defines lung cancer-associated FRC niches and key processes involved in stromal-T cell interaction that could pave the way for improved cancer immunotherapy.
2024-11-19 | E-MTAB-13708 | biostudies-arrayexpress
Project description:Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade (ICB), but understanding of their clinical significance and the circumstances of their resolution remains incomplete. Here, we found that in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse free survival. In areas of tumor regression, we further identified a non-canonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions, and increased expression of T cell memory markers. Collectively, these data suggest that TLS may serve be both a prognostic and predictive marker of response to immunotherapy in HCC and suggest a functional role for late-stage TLS T cell memory formation after elimination of viable tumor.
2024-09-13 | GSE272347 | GEO
Project description:Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade (ICB), but understanding of their clinical significance and the circumstances of their resolution remains incomplete. Here, we found that in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse free survival. In areas of tumor regression, we further identified a non-canonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions, and increased expression of T cell memory markers. Collectively, these data suggest that TLS may serve be both a prognostic and predictive marker of response to immunotherapy in HCC and suggest a functional role for late-stage TLS T cell memory formation after elimination of viable tumor.
2024-09-13 | GSE272346 | GEO