RESUMO
Treatments targeting the immune system only benefit a subset of patients with bladder cancer (BC). Biomarkers predictive of BC progression and response to specific therapeutic interventions are required. We evaluated whether peripheral blood immune subsets and expression of clinically relevant immune checkpoint markers are associated with clinicopathologic features of BC. Peripheral blood mononuclear cells isolated from blood collected from 23 patients with BC and 9 age-matched unaffected-by-cancer control donors were assessed using a 21-parameter flow cytometry panel composed of markers of T, B, natural killer and myeloid populations and immune checkpoint markers. Patients with BC had significantly lower numbers of circulating CD19+ B cells and elevated circulating CD4+CD8+ T cells compared with the control cohort. Immune checkpoint markers programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) were elevated in the total peripheral immune cell population in patients with BC. Within the BC cohort, PD-1 expression in T and myeloid cells was elevated in muscle-invasive compared with non-muscle-invasive disease. In addition, elevated T, B and myeloid PD-1 cell surface expression was significantly associated with tumor stage, suggesting that measures of peripheral immune cell exhaustion may be a predictor of tumor progression in BC. Finally, positive correlations between expression levels of the various immune checkpoints both overall and within key peripheral blood immune subsets collected from patients with BC were observed, highlighting likely coregulation of peripheral immune checkpoint expression. The peripheral blood immunophenotype in patients with BC is altered compared with cancer-free individuals. Understanding this dysregulated immune profile will contribute to the identification of diagnostic and prognostic indicators to guide effective immune-targeted, personalized treatments.
RESUMO
The complexity of the cellular and acellular players within the tumor microenvironment (TME) allows for significant variation in TME constitution and role in anticancer treatment response. Spatial alterations in populations of tumor cells and adjacent non-malignant cells, including endothelial cells, fibroblasts and tissue-infiltrating immune cells, often have a major role in determining disease progression and treatment response in cancer. Many current standard systemic antineoplastic treatments target the cancer cells and could be further refined to directly target commonly dysregulated cell populations of the TME. Recent developments in immuno-oncology and bioengineering have created an attractive potential to model these complexities at the level of the individual patient. These developments, along with the increasing momentum in precision medicine research and application, have catalysed exciting new discoveries in understanding drug-TME interactions, target identification, and improved efficacy of therapies. While rapid progress has been made, there are still many challenges to overcome in the development of accurate in vitro, in vivo and ex vivo models incorporating the cellular interactions that take place in the TME. In this review, we describe how advances in immuno-oncology and patient-derived models, such as patient-derived organoids and explant cultures, have enhanced the landscape of personalised immunotherapy prediction and treatment of solid organ malignancies. We describe and compare different immunological targets and perspectives on two-dimensional and three-dimensional modelling approaches that may be used to better rationalise immunotherapy use, ultimately providing a knowledge base for the integration of the autologous TME into these predictive models.