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Project description:Gene expression profiling of PD-1hi effector CD8+ T-cell after IL-10R blockade
| PRJNA398192 | ENA
Project description:Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1-induced human T-cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small cell lung cancer patients. Single cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+, but not CD28–CD8+ TILs, responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 co-stimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration, and loss of CD28 expression rather serve as a marker of anti-PD-1-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28–PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28–PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced proliferation of CD28–PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, we demonstrate loss of CD28 expression as a marker of PD-1 blockade-unresponsive human CD8+ TILs with TCF1– signature and provide mechanistic insights into combining IL-15 with anti-PD-1.
2020-05-01 | GSE145896 | GEO
Project description:While T cell accumulation in tumors is associated with response to immune checkpoint blockade (ICB), many T cell-rich tumors fail to respond to ICB. Here we leveraged a large neoadjuvant PD-1 blockade trial in hepatocellular carcinoma (HCC) to search for correlates of ICB response within T cell-rich tumors. Paired scRNAseq/TCRseq of nearly one million immune cells revealed that tumor responses to ICB correlated with significant clonal expansion of intratumoral CH25H+CXCL13+IL-21+CD4 T cells and GranzymeK+PD-1+CD8 effector T cells, whereas terminally exhausted CD39hiToxhiPD-1hi CD8 clones dominated in non-responders. Notably, proliferating and progenitor CD8 T cells clones were found in tumors of responders and non-responders. However, tumors from responders were highly enriched in mregDCs, a DC state triggered by capture of tumor debris, which formed physically interacting cellular triads with Tfh-like CD4 and progenitor-like CD8 T cells. Receptor-ligand analysis revealed unique interactions within these triads that may promote progenitor CD8 T cell differentiation into effector cells upon PD-1 blockade. These results suggest that discrete cellular niches that include mregDCs and Tfh-like CD4 T cells might control the differentiation of tumor-specific progenitor CD8 T cell clones into effective anti-tumor T cells in human tumors.
2023-06-16 | GSE206325 | GEO
Project description:Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggests a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
2020-05-01 | GSE148162 | GEO
Project description:The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of PD-1/PD-L1 blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL was a major positive costimulatory signal provided by these DCs within the TME, that translated to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlated with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME was associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy, and indicate a major role for the 4-1BB/4-1BBL axis during this process.
2024-05-13 | GSE238145 | GEO
Project description:Chronic lymphocytic leukaemia (B-CLL) is associated with immune suppression and functional impairment of NK cells, due partly to the reduced expression of activating receptors. We studied the profile of inhibitory checkpoint receptor expression on NK cells from patients with B-CLL. Single, dual and triple expression of the checkpoint receptors PD-1, CTLA-4, LAG-3 and CD96 was increased in patients compared to age-matched healthy controls. PD-1pos cells were present within the late differentiated CD56dim NK pool and showed strong downregulation of all activatory receptors whilst transcriptional profiles revealed a profile of strong receptor signalling. PD-1pos NK cells demonstrated impaired cytokine production and degranulation following target engagement and transfection of PD-1 into NK cell lines directed suppressed cytotoxic function. Importantly, blockade of PD-1:PD-L1 engagement acted to partially reverse these functional defects. These results reveal expression of inhibitory checkpoint receptors to be a new mechanism of NK cell dysfunction in patients with cancer and indicate a potential therapeutic role for single or combinatorial checkpoint blockade to boost immune function in patients with B-CLL.
2024-06-05 | GSE252613 | GEO
Project description:Clinical and translational results from a phase Ib trial testing whether IL-1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal anti-tumor T cell responses to PD-1 blockade.
2024-07-01 | GSE267814 | GEO
Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.
2021-10-12 | GSE178245 | GEO
Project description:The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade has resulted in a variety of preclinical investigations, yet the mechanism of action in humans remains unknown. We used scRNAsequencing and multi-spectral spatial imaging to elucidate the tumor immune microenvironment and correlates to response to a a unique open-label phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC)
2024-08-14 | GSE273138 | GEO
Project description:Adaptive immune escape of tumor cells by upregulation of ligands for programmed death 1 (PD-1) has been identified as an important and targetable pathway in many cancer types. Many clinical trials have demonstrated that targeting PD-1 or its ligand PD-L1 with immune checkpoint inhibitors (ICI) can restore anti-tumor immunity and induce durable remission. In patients with non-small cell lung cancer (NSCLC), several trials have demonstrated a survival benefit with ICI in patients with metastatic and locally advanced NSCLC.Yet, most patients have primary resistance to PD-1 or PD-L1 blockade during treatment: approximately 20% of unselected patients with NSCLC achieve a partial response while 40-50% have progressive disease as best response. Understanding mechanisms of primary resistance to PD-(L)1 blockade is important in the search for potentially targetable pathways and may ultimately allow discrimination between patients that benefit from PD-(L)1 blockade and those requiring combination or other approaches. We collected PBMCs and serum samples from 35 patients with NSCLC before and during PD-1 blockade treatment with nivolumab. We analyzed differentially expressed genes in CD8+ T cells from the peripheral blood of 5 patients with partial response and 5 patients with primary progressive disease to identify mechanisms of resistance to PD-1 therapy. Cells were collected from samples taken before and after 4 weeks of treatment.
2021-03-01 | GSE111414 | GEO