Project description:Recent studies revealed that treatment resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptide derived from tumor-associated antigens (TAAs), thus identification of tumor-associated antigens (TAAs) expressed in CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires large scale of sample and it is challenging for CSCs/CICs. In this study, we established novel bladder CSC/CIC model from a bladder cancer cell line UM-UC-3 cells using ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH) high cells and several ALDHhigh clone cells were established. ALDHhigh clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immune deficient mouse. HLA ligandome analysis and gene expression (CAGE) using ALDHhigh clone cells revealed distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we identified GRIK2 derived antigenic peptide is specifically expressed in CSCs/CICs. GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressed UM-UC-3 cells and ALDHhigh clone cells indicating that GRIK2 peptide can be a novel target for bladder CSCs/CICs-targeting immunotherapy. Overall design: Urothelial CSCs/CICs were isolated by an ALDEFLUOR assay fron human urothelial carcinoma cells, UM-UC-3. Aldehyde dehydrogenase-high (ALDHhigh) clone cell were isolated as urothelial CSCs/CICs. ALDHlow clone cells were isolated as urothelial non-CSCs/CICs. ALDHhigh clones (H-1, H-6, H-10) were used as CSCs/CICs clones and ALDHlow clones (L-1, L-3, L-8) were used as non-CSCs/CICs. Wild type UM-UC-3 cells were used as a control.
Project description:Bladder cancer is a highly metastatic tumor and one of the most common malignancies originating in the urinary tract. Despite the efficacy of immune checkpoints, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the effect of immunotherapy for bladder cancer remains unsatisfactory. Therefore, it is urgent to develop new targets to expand immunotherapeutic options. In this study, we utilized single-cell sequencing to explore the cell composition of tumors and detected a subset of Treg cells with high expression of T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and interleukin (IL)-32. The antitumor immune response was suppressed by this subset of Treg cells, while IL-32 promoted bladder cancer metastasis. Nevertheless, targeting TIGIT not only reversed immunosuppression by restoring the antitumor immune response mediated by T cells but also suppressed the secretion of IL-32 and inhibited the metastasis of bladder cancer cells. Thus, our study provided novel insights into immunosuppression in bladder cancer and highlighted TIGIT as a novel target for immunotherapy of bladder cancer. We also illustrated the mechanism of the dual effect of targeting TIGIT and revealed the metastasis-promoting effect of IL-32 in bladder cancer. Collectively, these findings raise the possibility of utilizing TIGIT as a target against bladder cancer from the bench to the bedside.
Project description:FGFR3 is a prognostic and predictive marker and is a validated therapeutic target in urothelial bladder cancer. Its utility as a marker and target in the context of immunotherapy is incompletely understood. We review the role of FGFR3 in bladder cancer and discuss preclinical and clinical clues of its effectiveness as a patient selection factor and therapeutic target in the era of immunotherapy.
Project description:There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades. While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma, unfortunately, only a minority of patients respond to immunotherapy. Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma. The first targeted therapy targeting the fibroblast growth factor receptor (FGFR) was recently approved for bladder cancer, but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations. Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials. Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer. Exploitation of androgen receptor (AR) is a potential strategy for targeted drug development in bladder cancer. A significant proportion of urothelial carcinoma patients express AR irrespective of gender. AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms, including activation of human epidermal growth factor receptor-2 (EGFR or HER-2) signaling and epithelial to mesenchymal transition (EMT). Furthermore, AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy. Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy. We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis, progression and its role as a novel therapeutic target and future directions.
Project description:Insulin-like growth factor binding protein-7 (IGFBP7) was recently reported to be a ligand of CD93, a potential target to normalize vasculature and attenuate immunotherapy. However, its role in the tumor microenvironment (TME) and immunotherapy response of bladder cancer (BLCA) remains unclear. We comprehensively evaluated the correlation between IGFBP7 and multiple immunological characteristics of BLCA across The Cancer Genome Atlas (TCGA) and two external cohorts. Importantly, the response of IGFBP7-grouped BLCA patients to immunotherapy was predicted and validated by five real-word immunotherapy cohorts. Finally, we developed an IGFBP7-based immune risk model validated by five independent cohorts. IGFBP7 modulated the TME across pan-caners. In BLCA, high expression of IGFBP7 was correlated with more aggressive clinical features. IGFBP7 was positively associated with immunomodulators and promoted tumor-infiltrating lymphocyte trafficking into the tumor microenvironment. However, T cells recognition and tumor cell killing were lower in the high-IGFBP7 group. In addition, high expression of IGFBP7 displayed lower enrichment scores for most pro-immunotherapy pathways. Clinical data from IMvigor210 and GSE176307 indicated that IGFBP7 negatively correlated with the BLCA immunotherapy response. The same trend was also observed in a renal cell carcinoma (RCC) cohort and two melanoma cohorts. Notably, urothelial and luminal differentiation were less frequently observed in the high-IGFBP7 group, while neuroendocrine differentiation was more frequently observed. Mechanistically, high IGFBP7 was associated with an enriched hypoxia pathway and higher expression of key genes in ERBB therapy and antiangiogenic therapy. Furthermore, our IGFBP7-based immune risk model was able to predict the prognosis and response to immunotherapy with good accuracy (5-year AUC = 0.734). Overall, IGFBP7 plays a critical role in the immunoregulation and TME of BLCA and may serve as a novel potential target for combination treatment with immunotherapy for BLCA.
Project description:A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multivariable linear regression (P = 6.46×10(-11); n = 278). The association pattern is similar in non-muscle-invasive tumors, stages Ta (P = 3.10×10(-5); n = 173) and T1 (P = 2.64×10(-5); n = 60), and muscle-invasive tumors, stages T2 (P =.01; n = 23) and T3/4 (P =.03; n = 22). The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. Future clinical studies will be needed to validate PSCA as a therapeutic target for bladder cancer.
Project description:The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.
Project description:Bladder cancer is a common malignant disease, with non-muscle-invasive bladder cancer (NMIBC) representing the majority of tumors. This cancer subtype is typically treated by transurethral resection. In spite of treatment, up to 70% of patients show local recurrences. Intravesical BCG (Bacillus Calmette-Guerin) immunotherapy has been widely used to treat NMIBC, but it fails to suppress recurrence of bladder tumors in up to 40% of patients. Therefore, the development of prognostic markers is needed to predict the progression of bladder cancer and the efficacy of intravesical BCG treatment. This study demonstrates the effectiveness of an E2F4 signature for prognostic prediction of bladder cancer. E2F4 scores for each sample in a bladder cancer expression dataset were calculated by summarizing the relative expression levels of E2F4 target genes identified by ChIP-seq, and then the scores were used to stratify patients into good- and poor-outcome groups. The molecular signature was investigated in a single bladder cancer dataset and then its effectiveness was confirmed in two meta-bladder datasets consisting of specimens from multiple independent studies. These results were consistent in different datasets and demonstrate that the E2F4 score is predictive of clinical outcomes in bladder cancer, with patients whose tumors exhibit an E2F4 score >0 having significantly shorter survival times than those with an E2F4 score <0, in both non-muscle-invasive, and muscle-invasive bladder cancer. Furthermore, although intravesical BCG immunotherapy can significantly improve the clinical outcome of NMIBC patients with positive E2F4 scores (E2F4>0 group), it does not show significant treatment effect for those with negative scores (E2F4<0 group).The E2F4 signature can be applied to predict the progression/recurrence and the responsiveness of patients to intravesical BCG immunotherapy in bladder cancer.
Project description:Recently, immunotherapy with checkpoint inhibitors has been showing promise in clinical trials for stage IV bladder cancer. Herein, we review the literature regarding the role for radiation therapy, the role for immunotherapy, and the potential synergy of these treatments combined in bladder cancer. There is ample pre-clinical data in a number of different tumor models, coupled with a growing body of clinical evidence in melanoma and other malignancies to suggest combining radiation and immunotherapy could lead to substantial advances in treatment outcomes for bladder cancer. Yet, these data for bladder cancer remain at the pre-clinical stage, and further study is needed.