NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer

Salome, B.; Sfakianos, J. P.; Daza, J.; Charap, A.; Hammer, C.; Banchereau, R.; Farkas, A. M.; Geanon, D.; Kelly, G.; de Real, R. M.; Lee, B.; Beaumont, K. G.; Shroff, S.; Wang, Y. S. A.; Wang, Y.-C.; Thin, T. H.; Garcia-Barros, M.; Hegewisch-Solloa, E.; Mace, E. M.; Wang, L.; O'Donnell, T.; Chowell, D.; Fernandez-Rodriguez, R.; Skobe, M.; Taylor, N.; Kim-Schulze, S.; Sebra, R. P.; Palmer, D.; Clancy-Thompson, E.; Hammond, S.; Kamphorst, A. O.; Malmberg, K.-J.; Marcenaro, E.; Romero, P.; Brody, R.; Viard, M.; Yuki, Y.; Martin, M.; Carrington, M.; Mehrazin, R.; Wiklund, P.; Mellman, I.; Mariath

doi:10.1101/2022.03.04.482960

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bioRxiv · 10.1101/2022.03.04.482960

NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer

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Abstract

PD-1/PD-L1-blockade immunotherapies have limited efficacy in the treatment of muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Here, we show that KLRC1 (NKG2A) expression associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in CD8Ahigh bladder tumors. The loss of antigen presentation is a common mechanism for tumor escape in bladder cancer. NKG2A+ CD8 T cells are able to circumvent HLA-ABC loss through TCR-independent cytotoxicity, which is partly mediated by DNAM-1. In bladder tumors, NKG2A is acquired on a subset of PD-1+ CD8 T cells, alongside stronger tissue-residency memory features, TCR-independent cytotoxicity and evidence of recent proliferation. HLA-E is low but variably expressed on bladder tumors. When expressed, NKG2A+ CD8 T cell anti-tumor responses to HLA-ABC-deficient tumors are inhibited and partly restored upon NKG2A blockade. Overall, our study identifies an alternative path for CD8 T cell exhaustion, that is mediated by NKG2A upregulation and TCR-independent cytotoxicity.

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Salome, B., Sfakianos, J. P., Daza, J., Charap, A., Hammer, C., Banchereau, R., Farkas, A. M., Geanon, D., Kelly, G., de Real, R. M., Lee, B., Beaumont, K. G., Shroff, S., Wang, Y. S. A., Wang, Y.-C., Thin, T. H., Garcia-Barros, M., Hegewisch-Solloa, E., Mace, E. M., Wang, L., O'Donnell, T., Chowell, D., Fernandez-Rodriguez, R., Skobe, M., Taylor, N., Kim-Schulze, S., Sebra, R. P., Palmer, D., Clancy-Thompson, E., Hammond, S., Kamphorst, A. O., Malmberg, K.-J., Marcenaro, E., Romero, P., Brody, R., Viard, M., Yuki, Y., Martin, M., Carrington, M., Mehrazin, R., Wiklund, P., Mellman, I., Mariath. 2022-03-05. NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer. https://doi.org/10.1101/2022.03.04.482960

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