Similar Datasets
Project description:Increased expression of mast cell related genes in melanoma tumors obtained from humanized mice after anti-PD-1 therapy.
2020-12-07 | GSE161351 | GEO
Project description:Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. [TCR]
| PRJNA674781 | ENA
Project description:Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.
| S-EPMC7804257 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-07 | GSE161353 | GEO
Project description:Metastatic uveal melanoma generally responds poorly to immunotherapy. The aim here was to sequence tumor-infiltrating lymphocytes from uveal melanoma metastases to study their phenotypes and T-cell receptor (TCR) clonotypes. We performed paired single-cell transcriptome and TCR sequencing using the 10x Genomics platform of IL2-expanded tumor-infiltrating lymphocytes from 7 liver and 1 subcutaneous metastasis.
2020-03-16 | E-MTAB-8846 | biostudies-arrayexpress
Project description:Background: Anti-tumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences. Methods: We developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous anti-tumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes. Results: We discovered that genetically identical wild-type recipient mice responded heterogeneously to the same SCC tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous anti-tumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRa/TCRb sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing vs. growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status. Conclusions: We reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous anti-tumor immune responses in different hosts. We suggest that anti-tumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.
2021-01-13 | GSE164153 | GEO
Project description:Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.
2023-08-01 | GSE234352 | GEO
Project description:The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown. Here, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCR-alpha-beta clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. Within CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression. Together, these findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct.
2023-11-15 | GSE246111 | GEO
Project description:Background: T-cell receptor (TCR) stimulation is essential to complete differentiation of tumor-infiltrating regulatory T cells (T-Tregs). Therefore, elucidation of TCR-dependent regulatory network involved in activation and proliferation of T-Tregs will facilitate discovery of novel antitumor remedy. Here, we investigated transcriptional features specific for antigen-reactive Tregs by harnessing single-cell RNA and TCR analyses of human Tregs derived from patients with non-small cell lung cancer (NSCLC). Methods: Assuming Tregs undergo clonal expansion in response to antigens, we sought for transcriptional features specific for antigen-reactive Tregs by comparing gene expression of Tregs with unique TCR clonotypes and those with expanded TCR clonotypes. To verify the identified molecule, multiplex immunohistochemistry and flow cytometry were used. Results: We found that the proportion of Tregs with expanded clonotypes was much higher in the tumor than in the periphery blood. We also found that T-Tregs with shared clonotypes were transcriptionally more similar to each other than to those with different clonotypes. Finally, we identified SYNGR2, TNFRSF18, DUSP4, and CTLA4 as core signature genes for T-Tregs with expanded clonotypes and confirmed their existences expressed on human T-Tregs. Interestingly, T-Treg-specific co-regulatory network revealed that SYNGR2, TNFRSF18 and DUSP4 are potential coordinators between TCR-dependent activation and cell proliferation. Conclusions: Our study shed light on regulatory insights of TCR-dependent Treg activation and differentiation in tumor and therapeutic strategies for patients with NSCLC.
2023-01-01 | GSE164146 | GEO
Project description:Clinical benefit from PD-1 inhibitors relies on reinvigoration of endogenous anti-tumor immunity. Efforts to define cellular populations associated with PD-1 clinical efficacy have been largely restricted to analysis of tumor material and the description of subsets of relevant cellular-based biomarkers in the blood of PD-1 inhibitor treated cancer patients are yet to be characterized. Given the particular expression pattern of PD-1 and TIGIT inhibitory receptors on peripheral CD8 T-cell subsets and the reported importance of CD8 T cells co-expressing these two markers for anti-PD-1 efficacy, we sought to determine the distinct biological features of peripheral CD8 subsets delineated based on PD-1 and TIGIT expression. Our findings identify the PD-1+TIGIT+ (DPOS) CD8+ T-cell population as a subset of highly activated and proliferating T cells, enriched in tumor-specific T-cell clones and overexpressing CXCR5, a key marker of the recently described CD8 cytotoxic follicular T cell (Tfc) population. Strikingly, the frequency of DPOS T cells after 1 month of anti-PD-1 therapy was associated with clinical response in three independent cohorts of cancer patients treated with PD-1 inhibitor. Additionally, transcriptomic profiling of this subset described common features with the PD-1high CXCL13+ lymphocyte subset previously demonstrated in tumor infiltrates to be predictive of PD-1 blockade efficacy. Furthermore, TCR repertoire analysis described a cluster of emerging T-cell clonotypes in the DPOS population as a key feature of PD-1 therapeutic efficacy.
2020-11-27 | GSE141120 | GEO