TY - JOUR
T1 - Mutant KRAS conversion of conventional T cells into regulatory T cells
AU - Zdanov, Stephanie
AU - Mandapathil, Magis
AU - Eid, Rasha Abu
AU - Adamson-Fadeyi, Saudat
AU - Wilson, Willie
AU - Qian, Jiahua
AU - Carnie, Andrea
AU - Tarasova, Nadya
AU - Mkrtichyan, Mikayel
AU - Berzofsky, Jay A.
AU - Whiteside, Theresa L.
AU - Khleif, Samir N.
N1 - Funding Information:
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (S.N. Khleif).
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016
Y1 - 2016
N2 - Constitutive activation of the KRAS oncogene in human malignancies is associated with aggressive tumor growth and poor prognosis. Similar to other oncogenes, KRAS acts in a cell-intrinsic manner to affect tumor growth or survival. However, we describe here a different, cell-extrinsic mechanism through which mutant KRAS contributes to tumor development. Tumor cells carrying mutated KRAS induced highly suppressive T cells, and silencing KRAS reversed this effect. Overexpression of the mutant KRASG12V gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-b1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway. Finally, we report that inhibition of KRAS reduces the infiltration of Tregs in KRAS-driven lung tumorigenesis even before tumor formation. This cell-extrinsic mechanism allows tumor cells harboring a mutant KRAS oncogene to escape immune recognition. Thus, an oncogene can promote tumor progression independent of its transforming activity by increasing the number and function of Tregs. This has a significant clinical potential, in which targeting KRAS and its downstream signaling pathways could be used as powerful immune modulators in cancer immunotherapy.
AB - Constitutive activation of the KRAS oncogene in human malignancies is associated with aggressive tumor growth and poor prognosis. Similar to other oncogenes, KRAS acts in a cell-intrinsic manner to affect tumor growth or survival. However, we describe here a different, cell-extrinsic mechanism through which mutant KRAS contributes to tumor development. Tumor cells carrying mutated KRAS induced highly suppressive T cells, and silencing KRAS reversed this effect. Overexpression of the mutant KRASG12V gene in wild-type KRAS tumor cells led to regulatory T-cell (Treg) induction. We also demonstrate that mutant KRAS induces the secretion of IL10 and transforming growth factor-b1 (both required for Treg induction) by tumor cells through the activation of the MEK-ERK-AP1 pathway. Finally, we report that inhibition of KRAS reduces the infiltration of Tregs in KRAS-driven lung tumorigenesis even before tumor formation. This cell-extrinsic mechanism allows tumor cells harboring a mutant KRAS oncogene to escape immune recognition. Thus, an oncogene can promote tumor progression independent of its transforming activity by increasing the number and function of Tregs. This has a significant clinical potential, in which targeting KRAS and its downstream signaling pathways could be used as powerful immune modulators in cancer immunotherapy.
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U2 - 10.1158/2326-6066.CIR-15-0241
DO - 10.1158/2326-6066.CIR-15-0241
M3 - Article
C2 - 26880715
AN - SCOPUS:85014918867
SN - 2326-6066
VL - 4
SP - 354
EP - 365
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 4
ER -
