PMID- 37014264
OWN - NLM
STAT- MEDLINE
DCOM- 20230602
LR  - 20231202
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 22
IP  - 6
DP  - 2023 Jun 1
TI  - BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to 
      Immune Checkpoint Blockade.
PG  - 751-764
LID - 10.1158/1535-7163.MCT-22-0369 [doi]
AB  - Non-T-cell-inflamed immunologically "cold" tumor microenvironments (TME) are 
      associated with poor responsiveness to immune checkpoint blockade (ICB) and can 
      be sculpted by tumor cell genomics. Here, we evaluated how retinoblastoma (Rb) 
      tumor-suppressor loss-of-function (LOF), one of the most frequent alterations in 
      human cancer and associated with lineage plasticity, poor prognosis, and 
      therapeutic outcomes, alters the TME, and whether therapeutic strategies 
      targeting the molecular consequences of Rb loss enhance ICB efficacy. We 
      performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on 
      the immune TME in human primary and metastatic tumors. Next, we used isogenic 
      murine models of Rb-deficient prostate cancer for in vitro and in vivo 
      mechanistic studies to examine how Rb loss and bromodomain and extraterminal 
      (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in 
      vivo therapeutic efficacy of BETi, singly and in combination with ICB and 
      androgen deprivation therapy. Rb loss was enriched in non-T-cell-inflamed tumors, 
      and Rb-deficient murine tumors demonstrated decreased immune infiltration in 
      vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced 
      tumor cell STING/NF-kappaB activation and type I IFN signaling within tumor cells, 
      resulting in differential macrophage and T-cell-mediated tumor growth inhibition 
      and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the 
      immunologically cold Rb-deficient TME via STING/NF-kappaB/IFN signaling to sensitize 
      Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale 
      to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate 
      cancer.
CI  - (c)2023 American Association for Cancer Research.
FAU - Olson, Brian M
AU  - Olson BM
AUID- ORCID: 0000-0003-1245-1004
AD  - Department of Hematology and Medical Oncology, Emory University, Atlanta, 
      Georgia.
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
FAU - Chaudagar, Kiranj
AU  - Chaudagar K
AUID- ORCID: 0000-0002-8113-8516
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
FAU - Bao, Riyue
AU  - Bao R
AUID- ORCID: 0000-0002-6105-1704
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
AD  - Center for Research Informatics, University of Chicago, Chicago, Illinois.
AD  - Department of Pediatrics, University of Chicago, Chicago, Illinois.
AD  - Cancer Bioinformatics Services, University of Pittsburgh Medical Center, 
      Pittsburgh, Pennsylvania.
FAU - Saha, Sweta Sharma
AU  - Saha SS
AUID- ORCID: 0000-0003-3591-653X
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
AD  - Translational and Clinical Research Institute, Newcastle University Centre for 
      Cancer, Newcastle upon Tyne, United Kingdom.
FAU - Hong, Christina
AU  - Hong C
AUID- ORCID: 0000-0003-1533-7098
AD  - Department of Hematology and Medical Oncology, Emory University, Atlanta, 
      Georgia.
FAU - Li, Marguerite
AU  - Li M
AUID- ORCID: 0000-0001-8098-6858
AD  - Department of Hematology and Medical Oncology, Emory University, Atlanta, 
      Georgia.
FAU - Rameshbabu, Srikrishnan
AU  - Rameshbabu S
AUID- ORCID: 0000-0002-9952-2591
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
FAU - Chen, Raymond
AU  - Chen R
AUID- ORCID: 0000-0002-2803-5163
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
FAU - Thomas, Alison
AU  - Thomas A
AUID- ORCID: 0000-0001-8924-1828
AD  - Department of Hematology and Medical Oncology, Emory University, Atlanta, 
      Georgia.
FAU - Patnaik, Akash
AU  - Patnaik A
AUID- ORCID: 0000-0001-5306-0208
AD  - Section of Hematology/Oncology, Departmentof Medicine, University of Chicago, 
      Chicago, Illinois.
LA  - eng
GR  - P30 CA138292/CA/NCI NIH HHS/United States
GR  - P50 CA180995/CA/NCI NIH HHS/United States
GR  - UL1 TR002378/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (NF-kappa B)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Androgen Antagonists)
SB  - IM
MH  - Male
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Prostatic Neoplasms/drug therapy/genetics
MH  - NF-kappa B
MH  - Immune Checkpoint Inhibitors
MH  - *Retinoblastoma
MH  - Androgen Antagonists
MH  - *Retinal Neoplasms
MH  - Tumor Microenvironment
PMC - PMC10239341
MID - NIHMS1890348
COIS- Conflicts of Interest: The authors declare no potential conflicts of interest.
EDAT- 2023/04/05 06:00
MHDA- 2023/06/02 06:42
PMCR- 2023/12/01
CRDT- 2023/04/04 10:12
PHST- 2022/05/25 00:00 [received]
PHST- 2023/01/09 00:00 [revised]
PHST- 2023/03/29 00:00 [accepted]
PHST- 2023/06/02 06:42 [medline]
PHST- 2023/04/05 06:00 [pubmed]
PHST- 2023/04/04 10:12 [entrez]
PHST- 2023/12/01 00:00 [pmc-release]
AID - 725051 [pii]
AID - 10.1158/1535-7163.MCT-22-0369 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2023 Jun 1;22(6):751-764. doi: 10.1158/1535-7163.MCT-22-0369.