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Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

ABSTRACT: Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR.

SUBMITTER: Vandeveer AJ

PROVIDER: S-EPMC4881865 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

Vandeveer Amanda J AJ Fallon Jonathan K JK Tighe Robert R Sabzevari Helen H Schlom Jeffrey J Greiner John W JW

Cancer immunology research 20160226 5

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of th ...[more]

PMID: 26921031

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Project description:BackgroundNon-muscle-invasive bladder cancer (NMIBC) is over three times as common in men as it is in women; however, female patients do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. Based on the established sexual dimorphism in mucosal immune responses, we hypothesized that the tumor immune microenvironment of bladder cancer differs between the sexes, and this may contribute to discrepancies in clinical outcomes.ObjectiveTo determine biological sex-associated differences in the expression of immune regulatory genes and spatial organization of immune cells in tumors from NMIBC patients.Design setting and participantsImmune regulatory gene expression levels in tumors from male (n = 357) and female (n = 103) patients were measured using whole transcriptome profiles of tumors from the UROMOL cohort. Multiplexe immunofluorescence was performed to evaluate the density and spatial distribution of immune cells and immune checkpoints in tumors from an independent cohort of patients with NMIBC (n = 259 males and n = 73 females).Outcome measurements and statistical analysisTranscriptome sequencing data were analyzed using DESeq2 in R v4.0.1, followed by application of the Kruskal-Wallis test to determine gene expression differences between tumors from males and females. Immunofluorescence data analyses were conducted using R version 3.5.3. Survival analysis was performed using survminer packages.Results and limitationsHigh-grade tumors from female patients exhibited significantly increased expression of B-cell recruitment (CXCL13) and function (CD40)-associated genes and the immune checkpoint genes CTLA4, PDCD1, LAG3, and ICOS. Tumors from female patients showed significantly higher infiltration of PD-L1+ cells and CD163+ M2-like macrophages than tumors from male patients. Increased abundance of CD163+ macrophages and CD79a+ B cells were associated with decreased recurrence-free survival.ConclusionsThese novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials in NMIBC.Patient summaryIn this study, we measured the abundance of various immune cell types between tumors from male and female patients with non-muscle-invasive bladder cancer. We demonstrate that tumors from female patients have a significantly higher abundance of immunosuppressive macrophages that express CD163. Higher abundance of tumor-associated CD163-expressing macrophages and B cells is associated with shorter recurrence-free survival in both male and female patients.

Dataset Information

Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

Publications

Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

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