Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

Abstract

Although Bacillus Calmette-Guérin (BCG) is the most successful immunotherapy for high-risk non-muscle-invasive bladder cancer, approximately 30% of patients are unresponsive to treatment. New biomarkers are important to identify patients who will benefit most from BCG during a worldwide BCG shortage. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded tissue sections of bladder cancer by immunohistochemistry, using monoclonal antibodies to tumor-associated macrophages (TAMs; CD68, CD163), B-lymphocytes (CD20) and T-lymphocyte subsets (CD3, CD4, CD8, GATA3, T-bet, FOXP3 and CD25). Cell densities in the lamina propria without invasion, at the invasive front if present, in the papillary tumor stroma, and in the neoplastic urothelium were calculated. Twenty-nine (72.5%) of 40 patients were classified as BCG responders after a mean follow-up of 35.3 months. A statistically significant association was observed for BCG failure with low density of CD4+ and GATA3+ T-cells, and increased expression of FOXP3+ and CD25+ regulatory T-cells (Tregs) as well as CD68+ and CD163+ TAMs. Survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with an increased count of CD4+ and GATA3+ T-cells. TAMs, Tregs and T-bet+ T-cells were inversely correlated with RFS. Thus, the tumor microenvironment seems to influence the therapeutic response to BCG, permitting an individualized treatment.

Intratumoral Th2 predisposition combines with an increased Th1 functional phenotype in clinical response to intravesical BCG in bladder cancer

“…Recently, we confirmed a Th2 predisposition (GATA3>T-bet) of tumor-infiltrating immune cells in high-risk NMIBC patients with response to BCG [30]. The aim of the present follow-up study was to examine the relation between such a Th2 predisposition and the actual functional phenotype during treatment as a potential biomarker of BCG response.…”

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

“…These macrophages play important roles in coordinating polarization of the immune response to either protect or attack the tumor. Pichler et al reported similar findings of an inverse correlation between tumor associated macrophages, T regs and T-bet + T-cells and disease free survival following BCG therapy [267]. High levels of CD4 + and GATA-3 + T cells were associated with improved disease free survival [267].…”

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

“…9 Tumors characterized by high CD4 + T cells, low regulatory T cells, and low CD68 + or CD163 + macrophages are associated with prolonged recurrence free survival in patients that responded to BCG therapy. 10 Thus, while the profile of anti-tumor and pro-tumor immune subsets in bladder cancer are predictive of clinical outcomes, the presence of TIL alone is not associated with the suppression of tumor growth.…”