Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells

Abstract

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 Treg induction. We also demonstrate that mutant KRAS induces the secretion of interleukin-10 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.

Kras mutation correlating with circulating regulatory T cells predicts the prognosis of advanced pancreatic cancer patients

“…It was reported that Kras mutation was associated with Tregs infiltration in various tumor tissues . Therefore, we analyzed the potential correlation between Kras mutation status and Tregs distribution in peripheral blood samples in advanced pancreatic cancer.…”

“…Abnormal distribution of T cell subsets such as high level of regulatory T cells (Tregs) and low level of cytotoxic T cells contributed to immunosuppressive environment in pancreatic cancer, and led to the escape of tumor cells from immune surveillance . It was reported that mutated Kras is associated with T cell differentiation and function in colorectal and lung cancers . Our previous study also found that Kras mutation correlates with Tregs infiltration in resectable pancreatic cancer tissues .…”

EGFR-targeted therapies in the post-genomic era

“…This improvement in survival from cetuximab was not seen for wild-type KRAS patients. In KRAS -variant patients, TFG-β1 was found to be upregulated; this cytokine has been implicated in suppressing antitumor immunity through regulatory T-cell induction [58]. Authors of this study proposed that through ADCC and improved dendritic cell priming of cytotoxic T lymphocytes, cetuximab bolstered the antitumor immunity otherwise inhibited in KRAS -variant patients [57].…”

Identification of Mutations, Expression Alterations and Fusion Transcripts by Next Generation RNAseq in Castration-Resistant Prostate Cancer Cell lines with Possible Clinical Relevance

“…RNAseq fastq data was aligned to reference genome hg38 by STAR 2 pass and GATK (base quality score recalibration, indel realignment, duplicate removal and INDEL discovery) was applied to call variants across all 15 samples according to GATK Best Practices recommendations [15][16][17]. A published TopHat and Cufflinks protocol was used to find differentially expressed genes [18] and ChimeraScan was employed to discover fusion transcripts [18].…”

“…GO term analysis showed that binding (GO: 0005488) and catalytic activity (GO:0003824) are two most widely distributed groups among all mutated genes ( Figure 1A), and the two most enriched pathways are 1) Immune response B cell antigen receptor (BCR) pathway, and 2) development positive regulation of STK3/4 (Hippo) pathway and negative regulation of YAP/TAZ function. Table 1: Selected mutated genes from 10 enriched pathways in Figure 1B [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”