PMID- 38542481
OWN - NLM
STAT- MEDLINE
DCOM- 20240329
LR  - 20240402
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 25
IP  - 6
DP  - 2024 Mar 20
TI  - KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like 
      Macrophage Phenotype.
LID - 10.3390/ijms25063510 [doi]
LID - 3510
AB  - Considerable advances have been made in lung cancer therapies, but there is still 
      an unmet clinical need to improve survival for lung cancer patients. 
      Immunotherapies have improved survival, although only 20-30% of patients respond 
      to these treatments. Interestingly, cancers with mutations in Kelch-like 
      ECH-associated protein 1 (KEAP1), the negative regulator of the nuclear factor 
      erythroid 2-related factor 2 (NRF2) transcription factor, are resistant to immune 
      checkpoint inhibition and correlate with decreased lymphoid cell infiltration. 
      NRF2 is known for promoting an anti-inflammatory phenotype when activated in 
      immune cells, but the study of NRF2 activation in cancer cells has not been 
      adequately assessed. The objective of this study was to determine how lung cancer 
      cells with constitutive NRF2 activity interact with the immune microenvironment 
      to promote cancer progression. To assess, we generated CRISPR-edited mouse lung 
      cancer cell lines by knocking out the KEAP1 or NFE2L2 genes and utilized a 
      publicly available single-cell dataset through the Gene Expression Omnibus to 
      investigate tumor/immune cell interactions. We show here that KEAP1-mutant 
      cancers promote immunosuppression of the tumor microenvironment. Our data suggest 
      KEAP1 deletion is sufficient to alter the secretion of cytokines, increase 
      expression of immune checkpoint markers on cancer cells, and alter recruitment 
      and differential polarization of immunosuppressive macrophages that ultimately 
      lead to T-cell suppression.
FAU - Occhiuto, Christopher J
AU  - Occhiuto CJ
AUID- ORCID: 0000-0002-2218-4504
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, MI 48824, USA.
AD  - Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 
      46202, USA.
FAU - Liby, Karen T
AU  - Liby KT
AUID- ORCID: 0000-0003-3317-3437
AD  - Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 
      46202, USA.
AD  - Department of Pharmacology and Toxicology, Indiana University School of Medicine, 
      Indianapolis, IN 46202, USA.
LA  - eng
GR  - R01 CA226690/CA/NCI NIH HHS/United States
GR  - GM142351/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20240320
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Keap1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - Lung/pathology
MH  - *Lung Neoplasms/pathology
MH  - NF-E2-Related Factor 2/metabolism
MH  - Phenotype
MH  - Tumor Microenvironment/genetics
PMC - PMC10970780
OTO - NOTNLM
OT  - KEAP1
OT  - M2 polarization
OT  - NRF2 pathway
OT  - immunosuppression
OT  - lung cancer
OT  - macrophages
COIS- C.J.O. reports no conflicts. K.T.L. is a named inventor on patents issued to 
      Dartmouth College for NRF2 activating synthetic triterpenoids and filed on behalf 
      of Michigan State University for NRF2 pathway inhibitors.
EDAT- 2024/03/28 06:45
MHDA- 2024/03/29 06:46
PMCR- 2024/03/20
CRDT- 2024/03/28 01:19
PHST- 2024/01/11 00:00 [received]
PHST- 2024/03/14 00:00 [revised]
PHST- 2024/03/17 00:00 [accepted]
PHST- 2024/03/29 06:46 [medline]
PHST- 2024/03/28 06:45 [pubmed]
PHST- 2024/03/28 01:19 [entrez]
PHST- 2024/03/20 00:00 [pmc-release]
AID - ijms25063510 [pii]
AID - ijms-25-03510 [pii]
AID - 10.3390/ijms25063510 [doi]
PST - epublish
SO  - Int J Mol Sci. 2024 Mar 20;25(6):3510. doi: 10.3390/ijms25063510.