Most bladder cancers are poorly responsive to immune checkpoint blockade (ICB). With the need to define mechanisms of de novo resistance, including contributions from the tumor microenvironment (TME), we used single-cell transcriptional profiling to map tumor infiltrating lymphocytic and myeloid cells in 10 human bladder tumors obtained from patients with a history of smoking either with or without previous ICB. Human data sets were qualitatively compared with single cell data sets from the BBN carcinogen induced mouse model of bladder cancer which was poorly responsive to PD-L1 blockade. We applied an established signature of acquired ICB resistance to these human and murine data sets to reveal conservation in EMT and TGF beta ICB resistance signatures between human-mouse stromal and myeloid cells. Using TCGA transcriptional data sets and deconvolution analysis we showed that patients with a history of smoking and bladder tumors high in M2 macrophage tumor content had a significantly worse survival outcome as compared to nonsmokers that were M2 high. Similarly, BBN induced tumors were high in M2 macrophage content and contained exhausted T-NK cells, thereby modeling the identified TCGA patient subpopulation. The combined targeting of TGF beta + PD-L1 reverted immune cell exclusion and resulted in increased survival and delayed BBN induced tumor progression. Together, these data support a coordinate role for stromal and myeloid cell populations in promoting de novo resistance to PD-L1 blockade particularly in patients with a history of smoking.

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