ABSTRACT
PURPOSE: Platinum-based chemotherapy and immune checkpoint inhibitors are key components of systemic treatment for muscle-invasive and advanced urothelial cancer. The ideal integration of these two treatment modalities remains unclear as clinical trials have led to inconsistent results. Modulation of the tumor-immune microenvironment by chemotherapy is poorly characterized. We aimed to investigate this modulation, focusing on potential clinical implications for immune checkpoint inhibitor response. EXPERIMENTAL DESIGN: We assessed immune cell densities, spatial relations, and tumor/stromal components from 116 patients with urothelial bladder cancer (paired data for 95 patients) before and after platinum-based chemotherapy. RESULTS: Several published biomarkers for immunotherapy response changed upon chemotherapy treatment. The intratumoral CD8+ T-cell percentage increased after treatment and was associated with increased TNFα-via-NF-κB signaling. The percentage of PDL1+ immune cells was higher after chemotherapy. An increase in chemo-induced changes that potentially inhibit an antitumor immune response was also observed, including increased fibroblast-based TGFß signaling and distances from immune cells to the nearest cancer cell. The latter two parameters correlated significantly in posttreatment samples, suggesting that TGFß signaling in fibroblasts may play a role in spatially separating immune cells from cancer cells. We examined specific chemotherapy regimens and found that treatment with methotrexate, vinblastine, doxorubicin, and cisplatin was associated with an increase in the macrophage cell percentage. Gemcitabine-containing chemotherapy was associated with upregulation of fibroblast TGFß signaling. CONCLUSIONS: The opposing effects of platinum-based chemotherapy on the immune cell composition and stromal context of the tumor-immune microenvironment may explain the inconsistent results of clinical trials investigating chemotherapy and immune checkpoint inhibitor combinations in bladder cancer.
Subject(s)
Biomarkers, Tumor , Tumor Microenvironment , Urinary Bladder Neoplasms , Humans , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effects , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Biomarkers, Tumor/metabolism , Female , Immunotherapy/methods , Male , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Aged , Middle Aged , Signal Transduction/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Stromal Cells/metabolism , Stromal Cells/drug effectsABSTRACT
Anti-PD1 and anti-PDL1 monotherapies have shown clinical efficacy in stage IV urothelial cancer and are integrated into current clinical practice. However, only a small number of the patients treated with single-agent checkpoint blockade experience an antitumour response. Insufficient priming or inhibitory factors in the tumour immune microenvironment might have a role in the lack of response. CTLA4 is an inhibitory checkpoint on activated T cells that is being studied as a therapeutic target in combination with anti-PD1 or anti-PDL1 therapies in advanced urothelial cancer. In locally advanced urothelial cancer, this combination approach has shown encouraging antitumour effects when administered pre-operatively. We believe that the presence of pre-existing intratumoural T cell immunity is not a prerequisite for response to combination therapy and that the additional value of CTLA4 blockade might involve the broadening of peripheral T cell priming, thereby transforming immunologically cold tumours into hot tumours.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , CTLA-4 Antigen , Urinary Bladder Neoplasms/drug therapy , T-Lymphocytes , Tumor MicroenvironmentABSTRACT
This study was performed to gain further insight in the heterogeneity of monocytes in the different categories of acute coronary syndrome (ACS), especially between patients with unstable angina pectoris, ST-elevation myocardial infarction (STEMI), and non-ST-elevation myocardial infarction (NSTEMI). For this purpose, blood samples were collected in the acute phase from patients presenting with an ACS. These samples were examined with multiparameter flow cytometry to identify the different monocyte subsets and to analyze the expression of monocyte-associated molecules. Leukocytes, as well as an absolute number of monocytes, showed a clear and significant increase in patients with STEMI. This increase was seen in all subtypes of monocytes. The classical monocytes (CD14++CD16-) of patients with an NSTEMI had a significantly increased CD11b expression when compared to the control group, while these cells showed a decreased expression pattern in STEMI patients. This increased CD11b-expression was also seen in the intermediate monocytes of NSTEMI, while it was almost completely downregulated on the intermediate monocytes of STEMI. Finally, CX3CR1, which is almost exclusively expressed on intermediate and nonclassical monocytes, showed a significant decrease in expression in patients with STEMI. In conclusion, intermediate and nonclassical monocytes have a different immunophenotypic pattern in patients with STEMI versus NSTEMI. These differences reflect the pro-inflammatory state of the monocytes in NSTEMI and can be used as target molecules for novel therapeutic strategies to diminish the migration of proinflammatory monocytes into the myocardial tissue. © 2017 International Society for Advancement of Cytometry.