Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells

Ailin Li; Hampartsoum B. Barsoumian; Jonathan E. Schoenhals; Taylor R. Cushman; Mauricio S. Caetano; Xiaohong Wang; David R. Valdecanas; Sharareh Niknam; Ahmed I. Younes; Guang Li; Wendy A. Woodward; Maria Angelica Cortez; James W. Welsh

doi:10.1016/j.canlet.2018.05.005

Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells

Ailin Li, Hampartsoum B. Barsoumian, Jonathan E. Schoenhals, Taylor R. Cushman, Mauricio S. Caetano, Xiaohong Wang, David R. Valdecanas, Sharareh Niknam, Ahmed I. Younes, Guang Li, Wendy A. Woodward, Maria Angelica Cortez, James W. Welsh

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80⁺Gr1^intCD11b⁺ myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8⁺ T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy.

Original language	English (US)
Pages (from-to)	54-63
Number of pages	10
Journal	Cancer Letters
Volume	431
DOIs	https://doi.org/10.1016/j.canlet.2018.05.005
State	Published - Sep 1 2018

Keywords

Anti-PD1 resistance
IDO1
Immunotherapy
Lung cancer
Myeloid-derived suppressor cells

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.canlet.2018.05.005

Cite this

Li, A., Barsoumian, H. B., Schoenhals, J. E., Cushman, T. R., Caetano, M. S., Wang, X., Valdecanas, D. R., Niknam, S., Younes, A. I., Li, G., Woodward, W. A., Cortez, M. A., & Welsh, J. W. (2018). Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells. Cancer Letters, 431, 54-63. https://doi.org/10.1016/j.canlet.2018.05.005

Li, A, Barsoumian, HB, Schoenhals, JE, Cushman, TR, Caetano, MS, Wang, X, Valdecanas, DR, Niknam, S, Younes, AI, Li, G, Woodward, WA, Cortez, MA & Welsh, JW 2018, 'Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells', Cancer Letters, vol. 431, pp. 54-63. https://doi.org/10.1016/j.canlet.2018.05.005

@article{e1e3e66a770a41a3b3d13705b12c2bf6,

title = "Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells",

abstract = "Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80+Gr1intCD11b+ myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8+ T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy.",

keywords = "Anti-PD1 resistance, IDO1, Immunotherapy, Lung cancer, Myeloid-derived suppressor cells",

author = "Ailin Li and Barsoumian, {Hampartsoum B.} and Schoenhals, {Jonathan E.} and Cushman, {Taylor R.} and Caetano, {Mauricio S.} and Xiaohong Wang and Valdecanas, {David R.} and Sharareh Niknam and Younes, {Ahmed I.} and Guang Li and Woodward, {Wendy A.} and Cortez, {Maria Angelica} and Welsh, {James W.}",

note = "Publisher Copyright: {\textcopyright} 2018",

year = "2018",

month = sep,

day = "1",

doi = "10.1016/j.canlet.2018.05.005",

language = "English (US)",

volume = "431",

pages = "54--63",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells

AU - Li, Ailin

AU - Barsoumian, Hampartsoum B.

AU - Schoenhals, Jonathan E.

AU - Cushman, Taylor R.

AU - Caetano, Mauricio S.

AU - Wang, Xiaohong

AU - Valdecanas, David R.

AU - Niknam, Sharareh

AU - Younes, Ahmed I.

AU - Li, Guang

AU - Woodward, Wendy A.

AU - Cortez, Maria Angelica

AU - Welsh, James W.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80+Gr1intCD11b+ myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8+ T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy.

AB - Indoleamine 2,3-dioxygenase 1 (IDO1), involved in the catabolism of tryptophan (Trp) to kynurenine (Kyn) is an important regulator of tumor-mediated immunosuppression implicated in resistance to anti-PD1 immunotherapy. We investigated the role of IDO1 in an anti-PD1-resistant lung cancer model (344SQ_R) compared to the parental 344SQ tumors (344SQ_P). IDO1 was overexpressed in tumor-infiltrating leukocytes, and plasma Kyn levels were increased, in 344SQ_R vs. 344SQ_P. The IDO1 inhibitor INCB023843 retarded tumor growth and reduced lung metastases in 344SQ_R. IDO1 was expressed at higher levels in F4/80+Gr1intCD11b+ myeloid-derived suppressor cells (MDSCs) that were prominent in 344SQ_R. The INCB023843 reduced IDO1 expression and percentages of these MDSCs while increasing CD8+ T cells infiltration, hence reactivating antitumor T-cell responses in 344SQ_R. Therefore, IDO1 inhibition holds promise for treating lung cancer that does not respond to anti-PD1 therapy.

KW - Anti-PD1 resistance

KW - IDO1

KW - Immunotherapy

KW - Lung cancer

KW - Myeloid-derived suppressor cells

UR - http://www.scopus.com/inward/record.url?scp=85047753382&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047753382&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2018.05.005

DO - 10.1016/j.canlet.2018.05.005

M3 - Article

C2 - 29746927

AN - SCOPUS:85047753382

SN - 0304-3835

VL - 431

SP - 54

EP - 63

JO - Cancer Letters

JF - Cancer Letters

ER -

Indoleamine 2,3-dioxygenase 1 inhibition targets anti-PD1-resistant lung tumors by blocking myeloid-derived suppressor cells

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this