| Autor: |
D. Ranti, Y.A. Wang, J. Daza, C. Bieber, B. Salomé, E. Merritt, J.A. Cavallo, E. Hegewisch-Solloa, E.M. Mace, A.M. Farkas, S. Shroff, F. Patel, M. Tran, T. Strandgaard, S. V. Lindskrog, L. Dyrskjøt, J. Qi, M. Patel, D. Geanon, G. Kelly, R.M. de Real, B. Lee, S. Kim-Schulze, T.H. Thin, M. Garcia-Barros, K.G. Beaumont, H. Ravichandran, Y. Hu, Y-C. Wang, L. Wang, D. LaRoche, Y. lee, R.P. Sebra, R. Brody, O. Elemento, A. Tocheva, B. D. Hopkins, P. Wiklund, J. Zhu, M.D. Galsky, N. Bhardwaj, J.P. Sfakianos, A. Horowitz |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.03.06.483198 |
| Popis: |
Mycobacterium bovis Bacillus Calmette-Guerin (BCG), the first-line treatment for non-muscle invasive bladder cancer (NMIBC), promotes the production of inflammatory cytokines, particularly interferon (IFN)-γ. Prolonged inflammation and IFN-γ exposure are known to cause an adaptive immune response, enabling immune escape and proliferation by tumor cells. We investigated HLA-E and NKG2A, a novel T and NK cell checkpoint pathway, as a driver of adaptive resistance in BCG unresponsive NMIBC. We observed ubiquitous inflammation in all patients after BCG immunotherapy, regardless of recurrence status. IFN-γ was shown to drive tumor expression of HLA-E and PD-L1. Further, NKG2A-expressing NK and CD8 T cells were enriched in BCG unresponsive tumors and with enhanced capacity for cytolytic functions. Strikingly, in situ spatial analyses revealed that HLA-EHIGH tumors are activated to recruit NK and T cells via chemokine production, potentially sparing HLA-ELOW tumors that would otherwise be susceptible to lysis. Finally, blood-derived NK cells retained anti-tumor functions at the time of tumor recurrence. These data support combined NKG2A and PD-L1 blockade for BCG unresponsive disease. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
