PMID- 36509363
OWN - NLM
STAT- MEDLINE
DCOM- 20230127
LR  - 20230201
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 555
DP  - 2023 Feb 28
TI  - PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer by 
      increasing immune infiltration.
PG  - 216034
LID - S0304-3835(22)00521-3 [pii]
LID - 10.1016/j.canlet.2022.216034 [doi]
AB  - Antitumor immunity requires lymphocytes to localize to the tumor. Prostate 
      cancers (PCs) are immunologically cold and tend to lack T-cell infiltration. Most 
      advanced PCs are insensitive to PD1 blockade therapies. Using syngeneic RM1 
      prostate tumors, p21-activated kinase-4 (PAK4) knockdown (KD) and pharmacological 
      inhibition was assessed in C57BL/6J mice treated with PD1 antibodies (alphaPD1). 
      RNASeq was used to characterize the immune response in the tumor. 
      Immunohistochemistry, flow cytometry, and in vivo blocking studies confirmed the 
      role of cell surface proteins in the generation of immune responses. In The 
      Cancer Genome Atlas, PAK4 expression was inversely correlated with immune cell 
      infiltration. PAK4 expression was controlled by the androgen receptor and its 
      pioneering factor, FOXA1. PAK4 KD increased CD8(+) T-cell infiltration and 
      expression of IFNgamma response genes. PAK4 KD also upregulated angiogenesis and 
      endothelial cell adhesion molecules in the tumor microenvironment, contributing 
      to CD8(+) lymphocyte recruitment. Pharmacological inhibition of PAK4 made PC more 
      responsive to immunotherapy with alphaPD1. A decrease in PAK4 activity increases 
      immune activation and vascularity, which increases CD8(+) lymphocyte infiltration 
      into the tumor. Therefore, targeting PAK4 may improve the response of human PC to 
      immunotherapy.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Su, Shengchen
AU  - Su S
AD  - Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los 
      Angeles, CA, 90048, USA. Electronic address: Shengchen.Su@cshs.org.
FAU - You, Sungyong
AU  - You S
AD  - Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los 
      Angeles, CA, 90048, USA. Electronic address: Sungyong.You@cshs.org.
FAU - Wang, Yanping
AU  - Wang Y
AD  - Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los 
      Angeles, CA, 90048, USA. Electronic address: Yanping.Wang@cshs.org.
FAU - Tamukong, Patrick
AU  - Tamukong P
AD  - Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los 
      Angeles, CA, 90048, USA. Electronic address: Patrick.Tamukong@cshs.org.
FAU - Quist, Michael J
AU  - Quist MJ
AD  - Cedars-Sinai Medical Center, Los Angeles, 8700 Beverly Blvd, Los Angeles, CA, 
      90048, USA. Electronic address: mjquist@gmail.com.
FAU - Grasso, Catherine S
AU  - Grasso CS
AD  - Cedars-Sinai Medical Center, Los Angeles, 8700 Beverly Blvd, Los Angeles, CA, 
      90048, USA. Electronic address: Catherine.Grasso@gmail.com.
FAU - Kim, Hyung L
AU  - Kim HL
AD  - Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los 
      Angeles, CA, 90048, USA. Electronic address: Hyung.KimL@cshs.org.
LA  - eng
PT  - Journal Article
DEP - 20221210
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - EC 2.7.11.1 (p21-Activated Kinases)
RN  - EC 2.7.11.1 (Pak4 protein, mouse)
RN  - 0 (Pdcd1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Male
MH  - Mice
MH  - CD8-Positive T-Lymphocytes
MH  - Cell Line, Tumor
MH  - Immunotherapy
MH  - Mice, Inbred C57BL
MH  - *p21-Activated Kinases/genetics/metabolism
MH  - *Prostatic Neoplasms/drug therapy/genetics
MH  - Tumor Microenvironment
OTO - NOTNLM
OT  - Checkpoint blockade
OT  - Combination immunotherapy
OT  - Immune infiltration
OT  - Prostate cancer
OT  - p21-activating kinases-4
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/12/13 06:00
MHDA- 2023/01/25 06:00
CRDT- 2022/12/12 19:27
PHST- 2022/07/25 00:00 [received]
PHST- 2022/11/09 00:00 [revised]
PHST- 2022/12/05 00:00 [accepted]
PHST- 2022/12/13 06:00 [pubmed]
PHST- 2023/01/25 06:00 [medline]
PHST- 2022/12/12 19:27 [entrez]
AID - S0304-3835(22)00521-3 [pii]
AID - 10.1016/j.canlet.2022.216034 [doi]
PST - ppublish
SO  - Cancer Lett. 2023 Feb 28;555:216034. doi: 10.1016/j.canlet.2022.216034. Epub 2022 
      Dec 10.