MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

Kitajima, Shunsuke; Tani, Tetsuo; Springer, Benjamin F.; Osaki, Tatsuya; Haratani, Koji; Chen, Minyue; Knelson, Erik H.; Mahadevan, Navin R.; Ritter, Jessica; Yoshida, Ryohei; Köhler, Jens; Ogino, Atsuko; Nozawa, Ryu-Suke; Sundararaman, Shriram K.; Thai, Tran C.; Homme, Mizuki; Piel, Brandon; Kivlehan, Sophie; Obua, Bonje; Purcell, Connor; Yajima, Mamiko; Barbie, Thanh U.; Lizotte, Patrick H.; Paweletz, Cloud P.; Gokhale, Prafulla C.; Barbie, David A.

doi:10.1016/j.ccell.2022.08.015

Cited by 38 publications

(21 citation statements)

References 66 publications

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“…After sensing cytosolic DNA, cGAS generates the second messenger 2’,3’-cGAMP, to phosphorylate STING. Activated STING further stimulates the expression of type I interferon genes and recruits T/NK cells to tumor microenvironment [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer

Liu

Xue

et al. 2023

BMC Cancer

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Background The kinesin-13 family member 2C (KIF2C) is a versatile protein participating in many biological processes. KIF2C is frequently up-regulated in multiple types of cancer and is associated with cancer development. However, the role of KIF2C in immune cell infiltration of tumor microenvironment and immunotherapy in breast cancer remains unclear. Methods The expression of KIF2C was analyzed using Tumor Immune Estimation Resource (TIMER) database and further verified by immunohistochemical staining in human breast cancer tissues. The correlation between KIF2C expression and clinical parameters, the impact of KIF2C on clinical prognosis and independent prognostic factors were analyzed by using TCGA database, the Kaplan-Meier plotter, and Univariate and multivariate Cox analyses, respectively. The nomograms were constructed according to independent prognostic factors and validated with C-index, calibration curves, ROC curves, and decision curve analysis. A gene set enrichment analysis (GSEA) was performed to explore the underlying molecular mechanisms of KIF2C. The degree of immune infiltration was assessed by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression (ESTIMATE) algorithm and the single sample GSEA (ssGSEA). The Tumor mutational burden and Tumor Immune Dysfunction and Rejection (TIDE) were used to analyze immunotherapeutic efficiency. Finally, the KIF2C-related competing endogenous RNA (ceRNA) network was constructed to predict the putative regulatory mechanisms of KIF2C. Results KIF2C was remarkably up-regulated in 18 different types of cancers, including breast cancer. Kaplan-Meier survival analysis showed that high KIF2C expression was associated with poor overall survival (OS). KIF2C expression was associated with clinical parameters such as age, TMN stage, T status, and molecular subtypes. We identified age, stage, estrogen receptor (ER) and KIF2C expression as OS-related independent prognosis factors for breast cancer. An OS-related nomogram was developed based on these independent prognosis factors and displayed good predicting ability for OS of breast cancer patients. Finally, our results revealed that KIF2C was significantly related to immune cell infiltration, tumor mutational burden, and immunotherapy in patients with breast cancer. Conclusion KIF2C was overexpressed in breast cancer and was positively correlated with immune cell infiltration and immunotherapy response. Therefore, KIF2C can serve as a potential biomarker for prognosis and immunotherapy in breast cancer.

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Section: Discussionmentioning

confidence: 99%

KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer

Liu

Xue

et al. 2023

BMC Cancer

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“…LKB1 is an important human tumor suppressor gene, and in non−small cell lung cancer (NSCLC) patients LKB1 mutations or genomic loss frequently co−occur with KRAS alterations. This combination results in a highly aggressive phenotype and reduced survival rate [ 28 , 29 , 30 ]. Most of the reports involving LKB1 have mainly concentrated on lung cancer, with limited reports on the role of LKB1 in GC.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Liver Kinase B1 (LKB1) in Gastric Cancer-Associated Tumor Microenvironment Immunity

Chen

Zhu

et al. 2023

Biomedicines

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Liver kinase B1 (LKB1) is a tumor suppressor gene, the inactivation of which occurs frequently in different tumor types. However, whether LKB1 is associated with the clinical features of gastric cancer (GC) and regulating tumor immunity is unknown. In this study, we showed that LKB1 is highly expressed in the serum of healthy individuals (n = 176) compared to GC patients (n = 416) and is also associated with clinical outcomes and good survival rates in GC patients. Furthermore, genes associated with immune checkpoints and T cell activation, such as PD−1, PD−L1, CD8A, CD8B, CD28, and GZMM, were shown to be highly expressed in GC subgroups with high LKB1 expression. Compared with fresh gastric cancerous tissues, LKB1 was highly expressed in CD3+CD8+ and CD3+CD8+CD28+ T cells in fresh adjacent non-cancerous tissues. CD3+CD8+ T cells produced an IFN−γ anti−cancer immune response. Furthermore, the proportion of CD3+CD8+ T cells that expressed LKB had a positive correlation with IFN−γ expression. Moreover, GC patients with low LKB1 expression had a poor objective response rate, and worse progression-free survival and overall survival when treated with pembrolizumab. In conclusion, LKB1 may be a potential immune checkpoint in GC patients.

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“…LKB1 was originally identi ed in 1997, and is also known as STK11 [27]. LKB1 is an important human tumor suppressor gene, and in non-small cell lung cancer (NSCLC) patients, LKB1 mutations or genomic loss frequently co-occur with KRAS alterations and this combination results in a highly aggressive phenotype and reduced survival rates [28][29][30]. Most of the reports on LKB1 mainly concentrated on lung cancer, with limited reports on the role of LKB1 in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of Liver kinase B1 (LKB1) in Gastric Cancers Associates with Tumor Microenvironment Immunity

Chen

Zhu

et al. 2022

Preprint

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Liver kinase B1 (LKB1) is a tumor suppressor gene whose inactivation occurs frequently in different tumor types. However, whether LKB1 associates with the clinical features of gastric cancer (GC) and regulates tumor immunity remains unknown. In this study, we found that LKB1 was highly expressed in the serum of healthy individuals (n = 176) compared with that of GC patients (n = 416), and was also associated with clinical outcomes and good survival rates in GC patients. Furthermore, genes associated with immune checkpoint and T cell activation, such as PD-1, PD-L1, CD8A, CD8B, CD28 and GZMM, were highly expressed in the GC subgroups with high LKB1 expression. Compared with fresh gastric cancerous tissue, LKB1 significantly high expressed in CD3 + CD8 + T cells and CD3 + CD8 + CD28 + T cells in fresh adjacent noncancerous tissues. CD3 + CD8 + T cells produced INF-γ anti-cancer immune response. Furthermore, CD3 + CD8 + T cells proportion which expressed of LKB, showed positive correction with INF-γ expression. Moreover, GC patients with low LKB1 expression showed a poor objective response rate and worse progression free survival and overall survival with pembrolizumab. In conclusion, these results suggest that LKB1 may be a potential immune checkpoint in GC patients.

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MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer

Cited by 38 publications

References 66 publications

KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer

KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer

Prognostic Value of Liver Kinase B1 (LKB1) in Gastric Cancer-Associated Tumor Microenvironment Immunity

Prognostic value of Liver kinase B1 (LKB1) in Gastric Cancers Associates with Tumor Microenvironment Immunity

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