scholarly journals Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer

2021 ◽  
Vol 13 (594) ◽  
pp. eabd1346
Author(s):  
Christopher S. Garris ◽  
Jeffrey L. Wong ◽  
Jeffrey V. Ravetch ◽  
David A. Knorr
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Mouse Models ◽  
Antitumor Immunity ◽  
Bladder Tumor ◽  
Immune Surveillance ◽  
Disease Recurrence ◽  
Bcg Therapy ◽  
Agonist Antibody

Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

scholarly journals Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

2021 ◽  
Vol 9 (3) ◽  
pp. e001941
Author(s):  
Niannian Ji ◽  
Neelam Mukherjee ◽  
Ryan M Reyes ◽  
Jonathan Gelfond ◽  
Martin Javors ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
Percentage Change ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Double Blind ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Muscle Invasive

BackgroundAlthough intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG’s antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.MethodsA randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.ResultsThirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1–2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: −26% (−51% to 24%) for placebo, 9.6% (−59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (−31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02).ConclusionsFour weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

scholarly journals CD8+ T Cell Co-Expressed Genes Correlate With Clinical Phenotype and Microenvironments of Urothelial Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Yutao Wang ◽  
Kexin Yan ◽  
Jiaxing Lin ◽  
Yang Liu ◽  
Jianfeng Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mhc Class I ◽  
Clinical Phenotype ◽  
Angiogenesis Inhibitors ◽  
Class I ◽  
T Cell Infiltration ◽  
Tumor Purity

PurposeTo identify immune-related co-expressed genes that promote CD8+ T cell infiltration in bladder cancer, and to explore the interactions among relevant genes in the tumor microenvironment.MethodWe obtained bladder cancer gene matrix and clinical information data from TCGA, GSE32894 and GSE48075. The “estimate” package was used to calculate tumor purity and immune score. The CIBERSORT algorithm was used to assess CD8+ T cell proportions. Weighted gene co-expression network analysis was used to identify the co-expression modules with CD8+ T cell proportions and bladder tumor purity. Subsequently, we performed correlation analysis among angiogenesis factors, angiogenesis inhibitors, immune inflammatory responses, and CD8+ T cell related genes in tumor microenvironment.ResultsA CD8+ T cell related co-expression network was identified. Eight co-expressed genes (PSMB8, PSMB9, PSMB10, PSME2, TAP1, IRF1, FBOX6, ETV7) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, and were enriched in the MHC class I tumor antigen presentation process. The proteins level encoded by these genes (PSMB10, PSMB9, PSMB8, TAP1, IRF1, and FBXO6) were lower in the high clinical grade patients, which suggested the clinical phenotype correlation both in mRNA and protein levels. These factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. PD-1 and PD-L1 positively correlated with these genes which suggested PD-1 expression level positively correlated with the biological process composed by these co-expression genes. In the high expression group of these genes, inflammation and immune response were more intense, and the tumor purity was lower, suggesting that these genes were immune protective factors that improved the prognosis in patients with bladder cancer.ConclusionThese co-expressed genes promote high levels of infiltration of CD8+ T cells in an immunoproteasome process involved in MHC class I molecules. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

scholarly journals Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment

2020 ◽  
Vol 3 (3) ◽  
pp. 179-192
Author(s):  
Sukhbir Kaur ◽  
Kyle V Cicalese ◽  
Rajdeep Banerjee ◽  
David D Roberts
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cytotoxic T Cells ◽  
Regulatory Protein ◽  
Immune Surveillance ◽  
Hematologic Malignancies ◽  
Clinical Development ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Thrombospondin 1

ABSTRACT CD47 is a ubiquitously expressed cell surface glycoprotein that functions as a signaling receptor for thrombospondin-1 and as the counter-receptor for signal regulatory protein-α (SIRPα). Engaging SIRPα on macrophages inhibits phagocytosis, and CD47 thereby serves as a physiological marker of self. However, elevated CD47 expression on some cancer cells also protects tumors from innate immune surveillance and limits adaptive antitumor immunity via inhibitory SIRPα signaling in antigen-presenting cells. CD47 also mediates inhibitory thrombospondin-1 signaling in vascular cells, T cells, and NK cells, and blocking inhibitory CD47 signaling on cytotoxic T cells directly increases tumor cell killing. Therefore, CD47 functions as an innate and adaptive immune checkpoint. These findings have led to the development of antibodies and other therapeutic approaches to block CD47 functions in the tumor microenvironment. Preclinical studies in mice demonstrated that blocking CD47 can limit the growth of hematologic malignancies and solid tumors and enhance the efficacy of conventional chemotherapy, radiation therapy, and some targeted cancer therapies. Humanized CD47 antibodies are showing promise in early clinical trials, but side effects related to enhanced phagocytic clearance of circulating blood cells remain a concern. Approaches to circumvent these include antibody preloading strategies and development of antibodies that recognize tumor-specific epitopes of CD47, SIRPα antibodies, and bivalent antibodies that restrict CD47 blockade to specific tumor cells. Preclinical and clinical development of antibodies and related biologics that inhibit CD47/SIRPα signaling are reviewed, including strategies to combine these agents with various conventional and targeted therapeutics to improve patient outcome for various cancers.

scholarly journals Epigenetic Reprogramming of CD4+ Helper T Cells as a Strategy to Improve Anticancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Elodie Renaude ◽  
Marie Kroemer ◽  
Christophe Borg ◽  
Paul Peixoto ◽  
Eric Hervouet ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Antitumor Immunity ◽  
Epigenetic Reprogramming ◽  
Helper T Cells ◽  
Epigenetic Factors ◽  
Epigenetic Drugs ◽  
Anticancer Immunotherapy

Evidences highlight the role of various CD4+ helper T cells (CD4+ Th) subpopulations in orchestrating the immune responses against cancers. Epigenetics takes an important part in the regulation of CD4+ Th polarization and plasticity. In this review, we described the epigenetic factors that govern CD4+ T cells differentiation and recruitment in the tumor microenvironment and their subsequent involvement in the antitumor immunity. Finally, we discussed how to manipulate tumor reactive CD4+ Th responses by epigenetic drugs to improve anticancer immunotherapy.

Bladder cancer: Predicting response to BCG.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 287-287
Author(s):  
Rafael Nunez-Nateras ◽  
Melissa L. Stanton ◽  
Erin N. Ferrigni ◽  
Cheryl A. Protheroe ◽  
Nancy A. Lee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Immune Responses ◽  
Immune Therapy ◽  
Therapy Response ◽  
Immunohistochemical Analysis ◽  
Standard Of Care ◽  
Eosinophil Infiltration ◽  
Th2 Immune Response ◽  
Bcg Therapy

287 Background: Our preliminary immunohistochemical studies of bladder cancer patients have shown that the inflammatory/immune responses associated with bladder cancer appear to be Th2-polarized as judged by the preponderance of tumor infiltrating GATA-3+ (Th2) vs. T-bet+ (Th1) T cells, as well as by evidence of tumor-associated eosinophil infiltration and activation. The standard-of-care treatment for Tis bladder cancer is intravesical administration of BCG, a Th1-polarizing immunomodulator. The aim of the present study was to assess the Th2/Th1 ratio correlation with response to BCG therapy in patients with Tis bladder cancer. Methods: Two groups of patients were studied. Group A included 20 patients that responded to BCG, and Group B included 20 patients that did not respond to therapy. Response to BCG was determined as presence/absence of disease at 6 months post-BCG therapy. The initial diagnostic biopsies of these patients were subjected to immunohistochemical analysis using commercially available antibodies specific for Th2 (GATA-3+) and Th1 (T-bet+) lymphocytes, and our unique monoclonal antibody specific for eosinophil peroxidase (EPX-mAb). Ten random high powered (400X) fields at the maximum focus of mononuclear infiltration were examined and the number of GATA 3+ and T-bet+ tumor infiltrating T cells were counted to define the G/T ratio for each patient sample. Eosinophils and their degranulation activity were counted in the same fields. Results: Patients with response to BCG therapy had a G/T ratio of ≥ 3 and patients with non-response to BCG therapy had a G/T ratio of ≤ 1.5. Correlation of these scores with subsequent patient outcomes following BCG immune therapy demonstrated that patient responsiveness (i.e., tumor elimination at 6 months) trended with the higher G/T ratio patients. In addition, initial biopsies of BCG responsive patients display a higher number of eosinophils and degranulation relative to BCG non-responsive patients. Conclusions: Evaluations of initial biopsies revealed a strong correlation between Th1 and Th2 immune response with BCG therapy outcomes. The development of specific and novel tools to identify/measure Th2 immune responses in Tis bladder cancer provides a unique opportunity to predict outcomes at the time of diagnosis.

A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS603-TPS603 ◽  
Author(s):  
Gary D. Steinberg ◽  
Joan Palou-Redorta ◽  
Juergen E. Gschwend ◽  
Ben Tran ◽  
Yohann Loriot ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Treatment Options ◽  
Complete Response ◽  
Disease Recurrence ◽  
Subsequent Treatment ◽  
Invasive Bladder Cancer ◽  
Open Label ◽  
Bcg Therapy ◽  
Us Fda ◽  
To Receive

TPS603 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC.1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.

TAMI-27. METABOLIC MANIPULATION OF T CELLS TO TREAT BRAIN TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi203-vi204
Author(s):  
Guimei Tian ◽  
Linchun Jin ◽  
Devshri Doshi ◽  
Aida Karachi ◽  
Mariana Dajac ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Brain Tumors ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Glucose Transporter ◽  
Glucose Transporters ◽  
Disease Recurrence

Abstract INTRODUCTION Glioblastoma are a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of- care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. OBJECTIVES The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T cells. The overall goal of this project is to test new treatments to reverse immune dysfunction in cancer through the regulation of T cell metabolic signaling. We propose that modulating glucose pathway in T cells can potentiate their anti-tumor activity once adoptively transferred. METHODS T cells glucose metabolic pathway was modulated via glucose transporters overexpression. The functionality of metabolically modified T cells was investigated in murine and human models. RESULTS We demonstrated the existence of a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T cell glucose utilization and provide survival/growth advantage and enhanced T cell activation in glucose-restricted conditions. We also established that glucose transporter overexpression improves intratumoral infiltration of adoptively transferred T cells. CONCLUSION This project integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.

Modulation of the RANK/RANKL/OPG system and FOXP3+ regulatory T cells in the tumor microenvironment of noninvasive bladder cancer after intravesical oncotherad immunotherapy associated with platelet-rich plasma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 462-462
Author(s):  
Bianca Ribeiro de Souza Sasaki ◽  
Ianny Brum Reis ◽  
Gabriela Oliveira ◽  
Nelson Duran ◽  
Wagner José Fávaro
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Tumor Progression ◽  
Platelet Rich Plasma ◽  
Low Grade ◽  
Antitumor Effects ◽  
Cancer Group ◽  
Muscle Invasive

462 Background: The activity of the receptor activator of nuclear factor-kβ RANK/RANKL in cancer cells has been correlated with tumor progression and poor prognosis in solid tumors including bladder cancer. Regulatory T cells (Tregs), often identified by FOXP3 biomarker, suppress the anti-tumor response and allow immune tolerance through suppression of T cells. Immunomodulator OncoTherad is an inorganic phosphate nanocomplex associated with glycosidic protein, developed by the University of Campinas/Brazil, with antitumor effects. Previous reports have demonstrated immune activation and antitumor effects of Platelet Rich Plasma (PRP). We evaluated the effects of OncoTherad associated with PRP in the RANK/RANKL system and Tregs in a mouse model of non-muscle invasive bladder cancer (NMIBC). Methods: C57BL/6J mice were assigned to groups (n = 42): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 consecutive weeks after induction. Results: After NMIBC induction, all animals in the Cancer group showed flat carcinoma in situ (pTis) and both percentages of RANK, RANKL, OPG, and FOXP3 positive cells and the intensity of immunoreaction for these antigens were significantly higher in comparison with healthy animals. In addition to ensuring this NMIBC model, these results indicated the involvement of RANK/RANKL in urothelial carcinogenesis and the presence of Tregs in a suppressed immune tumor microenvironment. Mice treated with PRP only showed a 28.6% rate of tumor progression inhibition (TPI) and exhibited papillary urothelial carcinoma (pTa) and pTis. In this group, the intensity of the RANKL and FOXP3 immunoreaction was weaker when compared to the Cancer group. Thus, PRP showed immunomodulatory effects, reducing Tregs that are sources of RANKL. Oncotherad immunotherapy led to an TPI of 85.7%, and benign flat hyperplasia was the most frequent diagnosis. Oncotherad reduced the total RANK and RANKL immunoreactivities and decreased the intensity of RANKL immunostaining in comparison to the Cancer. In the OncoTherad+PRP 10 mg/ml or 20 mg/ml group, TPI was 71.4%, with a predominance of non-malignant lesions such as flat hyperplasia, low-grade intraurothelial neoplasia, and reactive atypia. Treatments with Oncotherad and Oncotherad plus PRP decreased the percentage of FOXP3+ cells and reduced the intensity of FOXP3 immunoreaction compared to the Cancer and PRP groups. Conclusions: The tumor inhibition obtained with Oncotherad plus PRP was related to the alteration of the immune profile of the tumor microenvironment by decreasing RANK/RANKL expression and Tregs, resulting in an effective immune response against the tumor.

The Role of CXCL12-Mediated Aberrant Methylation and Tumor Microenvironment Remodeling in Carcinogenesis and Prognosis of Bladder Cancer

2021 ◽  
Author(s):  
Yiheng Du ◽  
Jin Cao ◽  
Xiang Jiang ◽  
Xiaowei Cai ◽  
Bo Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Bioinformatics Analysis ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Specific Marker ◽  
Cxcl12 Expression ◽  
Potential Association

Abstract Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have seen significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage bladder cancer at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) in bladder cancer is an essential player in patient's responsiveness to ICB therapy. Therefore, this manuscript explored the TME and identified CXCL12, a specific marker for inflammatory cancer associated fibroblasts(iCAFs), as potential molecular markers and therapeutic targets for bladder cancer. Methods We examined the gene expression profiles in the TCGA and GEO datasets to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of bladder cancer. Methylation analysis of CXCL12 was performed using the UALCAN and MethSurv databases. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. Bioinformatics analysis results were validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors Results Our analysis revealed the potential association between aberrant promoter methylation of CXCL12 and bladder cancer carcinogenesis. CpG sites methylation of the CXCL12 gene body was associated with bladder cancer prognosis. Moreover, the expression level of CXCL12 exhibited a significant correlation with patients' pathological features and prognosis. Through gene enrichment analysis, CXCL12 was demonstrated to be associated with immune modulation and tumor microenvironment remodeling. The MCP-COUNTER and ESTIMATE algorithms verified significant correlations between CXCL12 and TME components, particularly CAFs, macrophages, and T cells. The TIDE algorithm provided evidence that T-cell clearance and dysfunction were more pronounced in bladder cancers characterized by high CXCL12 expression and high iCAFs scores, contributing to inferior responsiveness to ICB therapy. Patients who expressed high CXCL12 levels and had high iCAFs scores were likely to have less frequent FGFR3 mutation and a stromal-rich molecular subtype. Immunohistochemistry revealed that the close association of CXCL12 with iCAFs in bladder cancer potentially influenced the intratumoral infiltration of CD8 + T cells. CXCL12 expression in MIBC was increased significantly in NMIBC, which supports the bioinformatics analysis results. The IMvigor210 cohort confirmed the iCAFs score to be significantly associated with the responsiveness to immune checkpoint blockade therapy. Conclusions This work explores carcinogenesis and cancer-promoting roles of CXCL12 in bladder cancer. As a specific marker gene of iCAFs, CXCL12 potentially promotes bladder cancer progression by regulating the tumor microenvironment. Further exploration of the association between CXCL12 and iCAFs may unravel potential therapeutic targets for bladder precision medicine and improve the responsiveness of immune checkpoint blockade therapy.

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