Tertiary lymphoid structure signatures are associated with survival and immunotherapy response in muscle-invasive bladder cancer.
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ABSTRACT:
SUBMITTER: Zhou L
PROVIDER: S-EPMC8143239 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The presence of B cells in tumors have been recently reported to predict the better prognosis of patients with cancer. B cells were found primarily in so-called tertiary lymphoid structures (TLSs) in tumor. TLSs are ectopic lymphoid aggregates that form at sites of micro-secondary lymphoid organs, including a B cell follicle with a network of follicular dendritic cells (FDCs) surrounded by T cell zone composed of CD4+ T follicular helper (Tfh) cells and CD8+ T cells and high endothelial venules (HEVs). The presence of TLS is associated with positive outcomes in several human malignancie and More importantly, TLSs enriched in B cells have been proven beneficial for response to ICB in multiple types of cancer. Here, we establish tobacco-associated HNSCC mouse model with TLS enrichment by overexpression of LIGHT in tumor to evaluate the TLS influence in HPV- HNSCC and immunotherapy in HPV- HNSCC.
2022-03-03 | GSE197559 | GEO
Project description:Radical cystectomy is the standard of care treatment for patients with localized muscle-invasive bladder cancer (MIBC). However, patients with MIBC experience high rates of relapse despite primary therapy, and perioperative strategy is an important treatment option. Cisplatin-based neoadjuvant chemotherapy was associated with improved prognosis, and adjuvant chemotherapy is also an important option for selected patients. However, perioperative chemotherapy is not effective in some patients. Moreover, the currently recommended perioperative treatment is cisplatin-based chemotherapy; approximately 50% of the patients are ineligilble for cisplatin treatment owing to various reasons such as medical comorbidities, poor performance status, and renal insufficiency. The recent success of treatment with immune checkpoint inhibitors (ICIs) suggests that ICIs is the new standard therapy for patients with metastatic bladder cancer. Furthermore, ICIs showed more favorable toxicity profiles than conventional cytotoxic chemotherapy. These results indicate that ICIs may play a role in the treatment of muscle-invasive disease, and many recent studies have been conducted in a perioperative setting. The present review aims to summarize and discuss the current perioperative strategy of immunotherapy focused on ICIs based on recent ongoing clinical trials.
| S-EPMC7807333 | biostudies-literature
Project description:Muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) are both major causes of morbidity and mortality. At diagnosis, MIBC is more likely to metastasize, but can often be treated with aggressive care. Standard treatment for MIBC patients is radical cystectomy but a select group of these individuals are not candidates for or will decline this treatment. Thus, bladder preservation therapy followed by combined chemoradiation may be considered. Despite the primary surgical management of MIBC, up to half of patients will obtain tumors at distant sites in the end and perioperative platinum-based chemotherapy comprises the standard of care. However, despite these aggressive treatment options, survival is poor and therefore, it is essential to combine local and systemic therapies. Therapeutic modalities contained cancer vaccines, immune checkpoint inhibitors and immunogenic therapy are emerging as alternatives to immunotherapy, and several drugs have recently been approved by the FDA. Currently, several trials of adjuvant immunotherapy based on checkpoint inhibitors that as monotherapy, inhibit the reaction between programmed death-receptor 1 (PD-1) and programmed death-receptor ligand 1 (PD-L1). Or combined therapies mixed with chemotherapy, radiation, or various immunotherapy are ongoing. This review summarizes the current state of immunotherapies and evolution of the chemotherapy landscape for MIBC perioperative treatment. Widespread research is currently being performed to investigate the role of perioperative immune checkpoint inhibition in both the neoadjuvant and adjuvant setting.
| S-EPMC8799279 | biostudies-literature
Project description:Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
| S-EPMC8762581 | biostudies-literature
Project description:Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC). Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint-relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy. Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p < 0.001). CD8+ T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%). Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.
| S-EPMC8740181 | biostudies-literature
Project description:The prediction of the response to Bacillus Calmette-Guerin (BCG) can help identify non-muscle-invasive bladder cancer (NMIBC) patients that may be better served with alternative therapy. Several cytokine profiles present promising results, but they are difficult to use in clinical practice. In this prospective, longitudinal study, we tried to identify reliable serum cytokines/chemokines to predict the response to BCG using samples collected before and during BCG induction therapy. We used the Bio-plex multiplex assays to identify potential BCG failure-related serum cytokines/chemokines in the discovery set (n = 13). After screening, we identified CCL27 as the top candidate biomarker for predicting the response to BCG (P = .003). In the validation set, we found that the AUC of the baseline CCL27 was 0.730 (95% CI 0.515-0.945, P = .040) along with 67% sensitivity, 78% specificity. The changes from baseline to last timepoint can also distinguish BCG responders from non-responders (AUC: 0.726, 95% CI 0.474-0.979, P = .044). Moreover, the combination score of serum CCL27 (CSCCL27), based on the baseline and changes of CCL27, could further improve the predictive accuracy with an AUC of 0.897 (95% CI 0.790-1.000, P < .001). The correlations between CCL27 and local/systemic immunologic parameters were further analyzed. The level of serum CCL27 was strongly correlated with regulatory T cells (Tregs) in the tumor microenvironment (P = .002), indicating that CCL27 may promote the recruitment of Tregs into the tumor microenvironment. Our results show that serum CCL27 may represent a practical and reliable marker for the prediction of the response to BCG in NMIBC.
| S-EPMC7458591 | biostudies-literature
Project description:Patients with non-muscle invasive bladder cancer (NMIBC) undergo lifelong monitoring based on repeated cystoscopy and urinary cytology due to the high recurrence rate of this tumor. Nevertheless, these techniques have some drawbacks, namely, low accuracy in detection of low-grade tumors, omission of pre-neoplastic lesions and carcinomas in situ (CIS), invasiveness, and high costs. This work aims to identify a urinary metabolomic signature of recurrence by proton Nuclear Magnetic Resonance (1H NMR) spectroscopy for the follow-up of NMIBC patients. To do this, changes in the urinary metabolome before and after transurethral resection (TUR) of tumors are analyzed and a Partial Least Square Discriminant Analysis (PLS-DA) model is developed. The usefulness of this discriminant model for the detection of tumor recurrences is assessed using a cohort of patients undergoing monitoring. The trajectories of the metabolomic profile in the follow-up period provide a negative predictive value of 92.7% in the sample classification. Pathway analyses show taurine, alanine, aspartate, glutamate, and phenylalanine perturbed metabolism associated with NMIBC. These results highlight the potential of 1H NMR metabolomics to detect bladder cancer (BC) recurrences through a non-invasive approach.
| S-EPMC6678457 | biostudies-literature
Project description:PurposeThis study was carried out to assess whether a prolonged time between primary transurethral resection of non-muscle-invasive bladder cancer (TURB) and implementation of bacillus Calmette-Guerin (BCG) immunotherapy (time to BCG; TTBCG) is associated with adverse oncological survival in patients with T1 high-grade (HG) non-muscle-invasive bladder cancer (NMIBC).Materials and methodsData on 429 patients from 13 tertiary care centers with primary T1HG NMIBC treated with reTURB and maintenance BCG between 2001 and 2019 were retrospectively reviewed. Change-point regression was applied following Muggeo's approach. The population was divided into subgroups according to TTBCG, whereas the recurrence-free survival (RFS) and progression-free survival (PFS) were estimated with log-rank tests. Additionally, Cox regression analyses were performed. Due to differences in baseline patient characteristics, propensity-score-matched analysis (PSM) and inverse-probability weighting (IPW) were implemented.ResultsThe median TTBCG was 95 days (interquartile range (IQR): 71-127). The change-point regression analysis revealed a gradually increasing risk of recurrence with growing TTBCG. The risk of tumor progression gradually increased until a TTBCG of approximately 18 weeks. When the study population was divided into two subgroups (time intervals: ≤ 101 and > 101 days), statistically significant differences were found for both RFS (p = 0.029) and PFS (p = 0.005). Furthermore, in patients with a viable tumor at reTURB, there were no differences in RFS and PFS. After both PSM and IPW, statistically significant differences were found for both RFS and PFS, with worse results for longer TTBCG.ConclusionThis study shows that delaying BCG immunotherapy after TURB of T1HG NMIBC is associated with an increased risk of tumor recurrence and progression.
| S-EPMC8332577 | biostudies-literature
Project description:Immunotherapy, in the form of immune checkpoint inhibitors (ICI), has shown activity in metastatic urothelial bladder carcinoma, resulting in the approval of several ICI agents in the first- and second-line settings. This has led to an increased interest in studying their efficacy in the neoadjuvant setting for muscle invasive disease - an area of significant unmet need. This non-systematic review will look at the evidence supporting the use of ICI in the neoadjuvant setting for this tumor, results of early-phase studies, ongoing trials, and possible future applications for these drugs.
| S-EPMC8273398 | biostudies-literature
Project description:Intravesical instillation of live attenuated bacillus Calmette-Guérin (BCG) is the gold standard for patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). BCG-failures include a heterogenous population of patients who share a designation of disease recurrence or progression following BCG and include patients with complete unresponsiveness to BCG, patients who respond initially but develop relapse and, in some cases, patients who are intolerant to BCG due to side effects. Given the efficacy and relatively rapid approval of several monoclonal antibodies against PD-L1 or PD-1 for advanced and metastatic bladder cancer, the role of these checkpoint inhibitors in BCG-relapsing disease at various disease stages is under consideration. Data supporting a role for immune checkpoint inhibitors is largely theoretical with limited supportive data from animal models and from clinical evidence of increased PD-L1 expression in BCG-unresponsive tumors. Current trials in BCG-unresponsive disease are underway and expected to provide insight regarding these concepts.
| S-EPMC6428193 | biostudies-literature