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Published on: October 30, 2013
Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer
Rei Kamitani1, Nobuyuki Tanaka1, Tadatsugu Anno1
1Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.
Insights
This study reveals bladder cancer (BC) immune microenvironment dynamics, identifying "hot" and "cold" tumor clusters. High-grade NMIBC patients in cold clusters face higher progression risk, suggesting new therapeutic targets for recurrent BC.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint inhibitors targeting PD-1/PD-L1 are used for bladder cancer (BC).
- The immune cell infiltration diversity and microenvironment dynamics in non-muscle-invasive BC (NMIBC) and its progression to muscle-invasive/metastatic disease are not well understood.
Purpose of the Study:
- To investigate the tumor immune microenvironment (TIM) in BC.
- To identify immune cell infiltration patterns and their association with disease progression and genetic alterations.
- To discover potential therapeutic targets for recurrent NMIBC, especially after BCG therapy.
Main Methods:
- Hierarchical clustering of 159 BC samples based on immune cell markers (CD3, CD4, CD8, FOXP3, CD20, PD-1, PD-L1, LAG3, TIGIT).
- Analysis of additional markers (CD39, CD44, CD68, CD163, IDO1, Ki67) and genetic alterations (RB1, TP53, FGFR3, KDM6A, KMT2A) using TCGA dataset.
- Evaluation of immune activity in recurrent tumors post-BCG therapy.
Main Results:
- Two clusters identified: "hot" (25%) with high immune marker expression and "cold" (75%) with low expression.
- Hot tumors showed higher expression of CD39, CD44, CD68, CD163, IDO1, and Ki67.
- High-grade T1 tumors were hotter; muscle-invasive tumors became colder.
- High-grade NMIBC in the cold cluster indicated a higher risk of disease progression.
- Specific genetic alterations (RB1, TP53 in hot; FGFR3, KDM6A, KMT2A in cold/intermediate) were linked to clusters.
- Immune activity was maintained in recurrent tumors after BCG therapy, with high FGFR3 in previously cold tumors.
Conclusions:
- The study elucidates the dynamic nature of the BC tumor immune microenvironment.
- Identified distinct immune profiles associated with BC progression and genetic alterations.
- Candidate molecules, like FGFR3, are proposed as therapeutic targets for recurrent NMIBC post-BCG therapy.
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