Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

El-Jawhari, Jehan J.; El-Sherbiny, Yasser M.; Scott, Gina B.; Morgan, Rhian; Prestwich, R.; Bowles, Paul A.; Blair, G. Eric; Tanaka, Tomoyuki; Rabbitts, Terence H.; Meade, Josephine L.; Cook, Graham P.

doi:10.1016/j.molimm.2013.11.020

Cited by 45 publications

(26 citation statements)

References 62 publications

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“…Our flow cytometric analysis revealed that the down‐regulation of MHC‐I expression by EGFR activation was dependent on the MEK‐ERK pathway, but not on the PI3K‐AKT pathway. Consistent with our in vitro findings, activation of the MEK‐ERK pathway or of its upstream activator RAS has previously been associated with low MHC expression in several other types of malignancy . MEK inhibition was also shown to increase MHC‐I expression in tumor cell lines .…”

Section: Discussionsupporting

confidence: 91%

“…Consistent with our in vitro findings, activation of the MEK-ERK pathway or of its upstream activator RAS has previously been associated with low MHC expression in several other types of malignancy. [25][26][27][28][29] MEK inhibition was also shown to increase MHC-I expression in tumor cell lines. 30 MHC-I expression has been found to be induced by tumor necrosis factor-α, interleukin-1, IFNβ, and IFNγ, all of which upregulate HLA-A through activation of the JAK-STAT pathway.…”

Section: Discussionmentioning

confidence: 96%

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Mutational activation of the epidermal growth factor receptor down‐regulates major histocompatibility complex class I expression via the extracellular signal‐regulated kinase in non–small cell lung cancer

et al. 2018

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The efficacy of programmed cell death–1 (PD‐1) blockade in patients with non–small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC‐I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC‐I expression in NSCLC cell lines. Appropriate EGFR‐TKIs increased MHC‐I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal–regulated kinase (ERK) kinase MEK, also increased MHC‐I expression, whereas the phosphatidylinositol 3‐kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK‐ERK pathway mediates the down‐regulation of MHC‐I expression in response to EGFR activation. Immunohistochemical analysis of EGFR‐mutated NSCLC specimens obtained before and after EGFR‐TKI treatment also revealed down‐regulation of phosphorylated forms of EGFR and ERK in association with up‐regulation of MHC‐I, an increased number of infiltrating CD8+ T cells, and increased PD‐1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC‐I expression through the MEK‐ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR‐MEK‐ERK signaling in and the immune response to EGFR‐mutated NSCLC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 96%

Mutational activation of the epidermal growth factor receptor down‐regulates major histocompatibility complex class I expression via the extracellular signal‐regulated kinase in non–small cell lung cancer

et al. 2018

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“…Since RAS signaling has been implicated in reducing the expression of genes involved in the presentation of antigens by MHC class I molecules ( Ebert et al., 2016 , El-Jawhari et al., 2014 ), we analyzed the expression of antigen processing and antigen presentation machinery following oncogenic RAS activation ( Figure S1 I). As expected, KRAS G12V signaling led to significant decreases in expression of TAP1 , TAPBP , as well as HLA-A , HLA-B , HLA-C , and B2M , suggesting that compromised antigen processing and presentation in concert with increases in PD-L1 expression may contribute to an augmented state of immunoresistance in RAS mutant tumor cells.…”

Section: Resultsmentioning

confidence: 99%

Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA

et al. 2017

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SummaryThe immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3′ UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers.

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“…Therefore, the possibility of a false negative is relatively small. Nevertheless, lymphocytes may affect the expression of KRAS gene in the ras signaling pathway,24 which suggests that an autoimmune lymphocyte response may inhibit KRAS gene mutation.…”

Section: Discussionmentioning

confidence: 99%

Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and <em>KRAS</em> mutation

Pang

et al. 2017

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The KRAS gene mutation is involved in several types of tumors. However, the potential role of the KRAS mutation in human primary and paired metastatic colorectal cancer (CRC) among different nationalities is poorly understood. In the present study, we assessed the relationship between KRAS mutation status and overall survival (OS) and disease-free survival (DFS) in 230 patients with primary and paired metastatic CRC. The KRAS mutation rate in primary CRC tissue was 43.0% (99/230), which was higher than in paired metastatic CRC, which was 31.9% (23/72; P<0.001). Clinicopathologically, the KRAS gene mutation rate was higher in tumors that had infiltrated more deeply (T3, T4) and in lymph node (LN) metastases (N1/N2) (P=0.029 and P=0.010, respectively). The KRAS gene status did not differ between the Han and Uyghur nationalities in both primary and metastatic CRC. In 72 paired cases, the KRAS mutation rate in primary CRC was significantly higher than in metastatic CRC (P<0.001) and in metastatic CRC that had infiltrated more deeply (T3, T4) (P=0.034). In the metastatic cases, the KRAS gene mutation rate was higher in patients aged over 65 years (P=0.035). Specifically, KRAS mutation was correlated with a poorer OS and DFS (P=0.004 and P=0.029, respectively). In our study, 35 patients with wild-type KRAS who received cetuximab targeted therapy had a better DFS than patients with mutant KRAS (P=0.029). The results of the current study demonstrate that the KRAS status is significantly associated with infiltrating LN metastases and the TNM stage in primary CRC. In addition, the results show that the KRAS mutation is significantly more common in primary tumors than in paired metastatic CRC, and the KRAS mutation is correlated with a shorter OS and DFS, as patients with wild-type KRAS who received cetuximab experienced a longer DFS.

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Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes

Cited by 45 publications

References 62 publications

Mutational activation of the epidermal growth factor receptor down‐regulates major histocompatibility complex class I expression via the extracellular signal‐regulated kinase in non–small cell lung cancer

Mutational activation of the epidermal growth factor receptor down‐regulates major histocompatibility complex class I expression via the extracellular signal‐regulated kinase in non–small cell lung cancer

Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA

Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and <em>KRAS</em> mutation

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