PMID- 38330013
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240219
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 121
IP  - 7
DP  - 2024 Feb 13
TI  - Enhancing cancer immunotherapy via inhibition of soluble epoxide hydrolase.
PG  - e2314085121
LID - 10.1073/pnas.2314085121 [doi]
LID - e2314085121
AB  - Cancer therapy, including immunotherapy, is inherently limited by chronic 
      inflammation-induced tumorigenesis and toxicity within the tumor 
      microenvironment. Thus, stimulating the resolution of inflammation may enhance 
      immunotherapy and improve the toxicity of immune checkpoint inhibition (ICI). As 
      epoxy-fatty acids (EpFAs) are degraded by the enzyme soluble epoxide hydrolase 
      (sEH), the inhibition of sEH increases endogenous EpFA levels to promote the 
      resolution of cancer-associated inflammation. Here, we demonstrate that systemic 
      treatment with ICI induces sEH expression in multiple murine cancer models. 
      Dietary omega-3 polyunsaturated fatty acid supplementation and pharmacologic sEH 
      inhibition, both alone and in combination, significantly enhance anti-tumor 
      activity of ICI in these models. Notably, pharmacological abrogation of the sEH 
      pathway alone or in combination with ICI counter-regulates an ICI-induced 
      pro-inflammatory and pro-tumorigenic cytokine storm. Thus, modulating endogenous 
      EpFA levels through dietary supplementation or sEH inhibition may represent a 
      unique strategy to enhance the anti-tumor activity of paradigm cancer therapies.
FAU - Kelly, Abigail G
AU  - Kelly AG
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Wang, Weicang
AU  - Wang W
AD  - Department of Entomology and Nematology, University of California, Davis, CA 
      95616.
AD  - University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817.
AD  - Department of Food Science, Purdue University, West Lafayette, IN 47907.
FAU - Rothenberger, Eva
AU  - Rothenberger E
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Yang, Jun
AU  - Yang J
AUID- ORCID: 0000-0001-8126-1728
AD  - Department of Entomology and Nematology, University of California, Davis, CA 
      95616.
AD  - University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817.
FAU - Gilligan, Molly M
AU  - Gilligan MM
AUID- ORCID: 0000-0002-7342-9858
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Kipper, Franciele C
AU  - Kipper FC
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Attaya, Ahmed
AU  - Attaya A
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Gartung, Allison
AU  - Gartung A
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Hwang, Sung Hee
AU  - Hwang SH
AD  - Department of Entomology and Nematology, University of California, Davis, CA 
      95616.
AD  - University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817.
FAU - Gillespie, Michael J
AU  - Gillespie MJ
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Bayer, Rachel L
AU  - Bayer RL
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Quinlivan, Katherine M
AU  - Quinlivan KM
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Torres, Kimberly L
AU  - Torres KL
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
FAU - Huang, Sui
AU  - Huang S
AD  - Institute of Systems Biology, Seattle, WA 98109.
FAU - Mitsiades, Nicholas
AU  - Mitsiades N
AD  - University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817.
AD  - Department of Internal Medicine, University of California Davis, CA 95817.
FAU - Yang, Haixia
AU  - Yang H
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
AD  - Department of Food Nutrition and Safety, College of Food Science and Nutritional 
      Engineering, China Agricultural University, Beijing 100083, China.
FAU - Hammock, Bruce D
AU  - Hammock BD
AUID- ORCID: 0000-0003-1408-8317
AD  - Department of Entomology and Nematology, University of California, Davis, CA 
      95616.
AD  - University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817.
FAU - Panigrahy, Dipak
AU  - Panigrahy D
AD  - Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 
      Harvard Medical School, Boston, MA 02215.
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA 02215.
AD  - Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 
      Boston, MA 02215.
LA  - eng
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - R35 ES030443/ES/NIEHS NIH HHS/United States
PT  - Journal Article
DEP - 20240208
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - 0 (Fatty Acids)
SB  - IM
CIN - Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2400431121. PMID: 38354255
MH  - Mice
MH  - Humans
MH  - Animals
MH  - *Epoxide Hydrolases/metabolism
MH  - Fatty Acids/metabolism
MH  - Inflammation/metabolism
MH  - *Neoplasms/therapy
MH  - Immunotherapy
MH  - Tumor Microenvironment
PMC - PMC10873624
OTO - NOTNLM
OT  - eicosanoid
OT  - immunonutrition
OT  - inflammation resolution
OT  - omega-3 fatty acids
OT  - soluble epoxide hydrolase
COIS- Competing interests statement:J.Y., S.H.H., and B.D.H. are affiliated with 
      EicOsis Human Health which has a sEH inhibitor in human 1b safety trials. J.Y., 
      S.H.H., and B.D.H. have stock options in EicOsis Human Health to disclose. The 
      authors disclose the following patent filing: E.R., S.H.H., B.D.H., and D.P. 
      Methods of Improving Cancer Immunotherapy. Provisional Application No. 63/326,504 
      filed April 1, 2022. Use of dual COX-2/sEH inhibitors with immunotherapy Use of 
      dual COX-2/sEH inhibitors with immunotherapy. D.P. has received consulting fees 
      from attorneys representing plaintiffs in cases involving exposure to chemical 
      agents. The other authors declare they have no actual or potential competing 
      financial interests.
EDAT- 2024/02/08 18:42
MHDA- 2024/02/09 06:42
PMCR- 2024/02/08
CRDT- 2024/02/08 13:43
PHST- 2024/02/09 06:42 [medline]
PHST- 2024/02/08 18:42 [pubmed]
PHST- 2024/02/08 13:43 [entrez]
PHST- 2024/02/08 00:00 [pmc-release]
AID - 202314085 [pii]
AID - 10.1073/pnas.2314085121 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2024 Feb 13;121(7):e2314085121. doi: 
      10.1073/pnas.2314085121. Epub 2024 Feb 8.