TY - JOUR
T1 - Myeloid cell–associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing
AU - Wang, Li
AU - Sfakianos, John P.
AU - Beaumont, Kristin G.
AU - Akturk, Guray
AU - Horowitz, Amir
AU - Sebra, Robert P.
AU - Farkas, Adam M.
AU - Gnjatic, Sacha
AU - Hake, Austin
AU - Izadmehr, Sudeh
AU - Wiklund, Peter
AU - Oh, William K.
AU - Szabo, Peter M.
AU - Wind-Rotolo, Megan
AU - Unsal-Kacmaz, Keziban
AU - Yao, Xin
AU - Schadt, Eric
AU - Sharma, Padmanee
AU - Bhardwaj, Nina
AU - Zhu, Jun
AU - Galsky, Matthew D.
N1 - Funding Information:
The results shown here are, in part, based upon data generated by TCGA research network: http://cancergenome.nih.gov/. We thank Jill Gregory at the Icahn School of Medicine Instructional Technology Group for assistance with graphic design. This work was supported by CA196521 (to M.D. Galsky, N. Bhardwaj, and W.K. Oh) and NIH Loan Repayment Program (to S. Izadmehr).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Purpose: To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer. Experimental Design: We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures. Results: We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (Msc2IR) score. Single myeloid phagocytic cells with low Msc2IR scores demonstrated upregulation of proinflammatory cytokines/ chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade–resistant metastatic urothelial cancer. Conclusions: The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
AB - Purpose: To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer. Experimental Design: We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures. Results: We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (Msc2IR) score. Single myeloid phagocytic cells with low Msc2IR scores demonstrated upregulation of proinflammatory cytokines/ chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade–resistant metastatic urothelial cancer. Conclusions: The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
UR - http://www.scopus.com/inward/record.url?scp=85111676485&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4574
DO - 10.1158/1078-0432.CCR-20-4574
M3 - Article
C2 - 33837006
AN - SCOPUS:85111676485
SN - 1078-0432
VL - 27
SP - 4287
EP - 4300
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -