Year-end Sale % OFF 
Abstract
Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8+ T cell infiltration has been proposed as a putative biomarker for response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking. The major aims of this study were to explore spatial heterogeneity for lymphocyte infiltration and to investigate how the immune landscape changes during the disease course. We performed multiplex immunohistochemistry to assess the density of intratumoral and stromal CD3+, CD8+, FoxP3+ and CD20+ immune cells in longitudinally collected samples of 49 UC patients. Within these samples, spatial heterogeneity for lymphocyte infiltration was observed. Regions the size of a 0.6 tissue microarray core (0.28 mm2) provided a representative sample in 60.6 to 71.6% of cases, depending on the cell type of interest. Regions of 3.30 mm2, the median tumor surface area in our biopsies, were representative in 58.8 to 73.8% of cases. Immune cell densities did not significantly differ between untreated primary tumors and metachronous distant metastases. Interestingly, CD3+, CD8+ and FoxP3+ T cell densities decreased during chemotherapy in two small cohorts of patients treated with neoadjuvant or palliative platinum-based chemotherapy. In conclusion, spatial heterogeneity in advanced UC challenges the use of immune cell infiltration in biopsies as biomarker for response prediction. Our data also suggests a decrease in tumor-infiltrating T cells during platinum-based chemotherapy.
Highlights
Whereas cisplatin-based chemotherapy remains the standard first-line treatment for patients with metastatic urothelial cancer (UC), immune checkpoint inhibitors have become available as an additional treatment option for these patients in the last few years
In three cases the origin of the metastases was unclear, because the patient presented with metastatic disease without a detectable primary tumor (n=1) or because the patient had a history of both invasive UC of the bladder and upper urinary tract (n=2)
Pairwise comparisons revealed that the densities of intratumoral CD3+ and FoxP3+ T cells were significantly higher in lymph node metastases compared to bone metastases (CD3+ cells: p=0.025; FoxP3+: p=0.0006) or tumors located in the urinary tract (CD3+ cells: p=0.022; FoxP3+: p=0.0041)
Summary
Whereas cisplatin-based chemotherapy remains the standard first-line treatment for patients with metastatic urothelial cancer (UC), immune checkpoint inhibitors have become available as an additional treatment option for these patients in the last few years. A phase III trials in patients with localized muscle-invasive UC has shown that nivolumab improves disease-free survival in the adjuvant setting (20.8 versus 10.8 months) [3]. In light of these developments, there is a need for a thorough understanding on how the responsiveness to checkpoint inhibitors in UC changes during the disease course and whether or not the immune infiltrate can be used to predict response to checkpoint inhibitors
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
