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.
We assessed immune cell densities, spatial relations, and tumor/stromal components from 116 urothelial bladder cancer patients (paired data for 95 patients), before and after platinum-based chemotherapy.
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-NFκB signaling. The percentage of PD-L1+ immune cells was higher after chemotherapy. An increase in chemo-induced changes that potentially inhibit an anti-tumor immune response was also observed, including increased fibroblast-based TGF-β signaling and distances from immune cells to the nearest cancer cell. The latter two parameters correlated significantly in post-treatment samples, suggesting that TGF-β signaling in fibroblasts may play a role in spatially separating immune cells from cancer cells. We examined specific chemotherapy regimens and found that MVAC was associated with an increase in the macrophage cell percentage. Gemcitabine-containing chemotherapy was associated with upregulation of fibroblast TGF-β signaling.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Jul 24 [Epub ahead of print]
Maksim A Chelushkin, Jeroen van Dorp, Sandra van Wilpe, Iris M Seignette, Jan-Jaap J Mellema, Maartje Alkemade, Alberto Gil-Jimenez, Dennis Peters, Wim Brugman, Chantal F Stockem, Erik Hooijberg, Annegien Broeks, Bas W G van Rhijn, Laura S Mertens, Antoine G Van der Heijden, Niven Mehra, Maurits L van Montfoort, Lodewyk F A Wessels, Daniel J Vis, Michiel S Van der Heijden
The Netherlands Cancer Institute, Amsterdam, Netherlands., Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands., Netherlands Cancer Institute, Amsterdam, Netherlands., The Netherlands Cancer Institute, Netherlands., Netherlands Cancer Institute, Netherlands., Antoni van Leeuwenhoek Hospital, Amsterdam, NH, Netherlands., Radboud University Medical Centre, Nijmegen, The Netherlands., Nijmegen, Netherlands., The Netherlands Cancer Institute, Amsterdam, NH, Netherlands., Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Netherlands.