TY - JOUR
T1 - Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells
AU - Zdanov, Stephanie
AU - Mandapathil, Magis
AU - Abu Eid, Rasha
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 - Grant Support
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (S.N. Khleif).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
PY - 2016/4
Y1 - 2016/4
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 KRAS(G12V)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-β1 (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 KRAS(G12V)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-β1 (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.
KW - Research Support, N.I.H., Intramural
U2 - 10.1158/2326-6066.CIR-15-0241
DO - 10.1158/2326-6066.CIR-15-0241
M3 - Article
C2 - 26880715
VL - 4
SP - 354
EP - 365
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 4
ER -