The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity

Liu, Chengming; Zheng, Sufei; Jin, Runsen; Wang, Xinfeng; Wang, Rui; Zang, Ruochuan; Xu, Haiyan; Lu, Zhiliang; Huang, Jianbing; Lei, Yuanyuan; Mao, Shuangshuang; Wang, Yalong; Feng, Xiaoli; Sun, Nan; Wang, Yan; He, Jie

doi:10.1016/j.canlet.2019.10.027

Cited by 225 publications

(178 citation statements)

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“…Up-regulated PD-1 on T cells inhibits T cell differentiation to effector T cells and promotes T cell apoptosis. A previous study showed that oncogenic KRAS increases tumor PD-L1 expression and promotes CD8 + cells infiltration to the tumor stroma (22). In our study, we did not observe that KRAS mutation increased PD-L1 expression ( Supplementary Figure 1C), nor a solid correlation of ACAA1 with PD-L1 expression in cancer cells using GEPIA (TCGA datasets) (Supplementary Figure 1D).…”

Section: Acaa1 Is a Biomarker Of T Cell Exhaustion In Lusccontrasting

confidence: 64%

“…Recent studies indicated that NSCLC harboring KRAS mutation show higher clinical response rate to and efficacy of PD-1/PD-L1 blockade (22,23). However, the potential underlying mechanisms are still obscure.…”

Section: Discussionmentioning

confidence: 99%

“…Oncogenic KRAS enhances immune checkpoint inhibitor efficacy by providing an inflammatory tumor microenvironment (24). Additionally, oncogenic KRAS also increases tumor PD-L1 expression and promotes CD8 + cells infiltration into the tumor stroma (22). Moreover, NSCLC harboring KRAS mutation present a higher tumor mutation burden, leading to tumor immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

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ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

Feng

Shen

2020

Front. Oncol.

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Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancers. KRAS mutation is the second most prevalent mutation in NSCLC. KRAS mutant cancer cells suppress the anti-tumor T cell response. However, the underlying mechanism is still unknown. Here, we analyzed the differential expression of acetyl-CoA acyltransferase 1 (ACAA1) in various types of cancers using the TIMER database and validated the results in the NSCLC cell line H1944. We silenced oncogenic KRAS by siRNA targeting KRAS G13D , and employed an MAPK signaling pathway inhibitor to clarify the possible regulatory pathway. Moreover, we analyzed the correlation of ACAA1 expression level with B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. Correlations between expression of ACAA1 and several biomarkers of mutation burden were also tested. Finally, we evaluated the prognostic value of ACAA1 in a wide range of cancers using the Kaplan-Meier Plotter Database. We found lower expression of ACAA1 in tumor tissue than in adjacent normal tissue in various cancers. This result was confirmed using a GEO dataset. Knock-down of mutant KRAS resulted in increased ACAA1 mRNA level in H1944 cells. ACAA1 mRNA level was significantly upregulated in H1944 after treatment with MAPK pathway inhibitor sorafenib, indicating that oncogenic KRAS may downregulate ACAA1 through MAPK signaling. ACAA1 was negatively correlated with biomarkers of tumor mutation burden, including BRCA1, ATM, ATR, CDK1, PMS2, MSH2, and MDH6. Conversely, ACAA1 expression was positively correlated with infiltrating CD4 + cells and with Th1, Th2, Treg cells in the lung tumor microenvironment. Finally, we showed that ACAA1 is a predictive factor for survival in several cancer types. In summary, decreased ACAA1 expression is correlated with poor prognosis and decreases immune infiltration of CD4 + T cells in LUAD and LUSC. ACAA1 also predicts T cell exhaustion in LUSC. The mechanism underlying KRAS/ACAA1 axis-mediated regulation of immune cell infiltration requires further investigation.

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Section: Acaa1 Is a Biomarker Of T Cell Exhaustion In Lusccontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

Feng

Shen

2020

Front. Oncol.

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“…Recent studies have reported KRAS-mutant tumors to show greater PD-L1 expression (23) and T-cell infiltration (24). Here, our analysis of the correlation between KRAS mutation status and TMB revealed TMB to be associated with tumor immunogenicity and greater benefit of ICI therapy (25).…”

Section: Discussionmentioning

confidence: 60%

A Potential Biomarker of Combination of Tumor Mutation Burden and Copy Number Alteration for Efficacy of Immunotherapy in KRAS-Mutant Advanced Lung Adenocarcinoma

Xiang

Wang

et al. 2020

Front. Oncol.

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Objectives: The Kirsten Rat Sarcoma (KRAS) mutation is the commonest oncogenic drive mutation in lung adenocarcinoma (LUAD) and immunotherapy may be quite promising for KRAS-mutant LUAD. While the effects of tumor mutation burden (TMB) and copy number alteration (CNA) are poorly understood in this illness, our study aimed to explore the roles TMB and CNA play in the prediction of response to immune checkpoint inhibitor (ICI) therapy in advanced KRAS-mutant LUAD. Methods: Mutation and clinical data were downloaded from cBioPortal. We evaluated KRAS mutation status and divided patients into different subgroups based on TMB and CNA cutoffs to investigate the predictive value of these biomarkers on ICI response. Results: KRAS mutation with concurrent TP53 or STK11 mutations had higher TMB and CNA compared to KRAS mutation alone. The KRAS G12C and G > T mutation subgroups, with TP53 or STK11 co-mutation, also had higher TMB and CNA. We found that TMB and CNA were independently associated with progression-free survival (PFS) and durable clinical benefits (DCB); TMB was positively correlated with PFS (P = 0.0074) and DCB (P = 0.0008) while low CNA was associated with prolonged PFS (P = 0.0060) and DCB (P = 0.0018). However, TMB alone did not distinguish benefits among KRASmutant patients. Notably, when combining TMB and CNA, low TMB and high CNA revealed worse outcomes of ICI therapy (mPFS: 2.20m, P = 0.0023; proportion of DCB: 24%, P = 0.0001). Conclusion: The combination of TMB and CNA provides more sensible and accurate prediction of ICI response than individual factors in KRAS-mutant LUAD. Moreover, low TMB and high CNA can be utilized as a potential biomarker to predict adverse outcome in KRAS-mutant LUAD.

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“…1 Traditional treatment, such as surgical resection, chemotherapy, had obvious limitations in recurrence and distant metastasis. Recently immunotherapy seems to be the potential and effective treatment in various cancers [2][3][4][5][6][7][8][9][10] , including colon cancer 7 . However, only about 20% of patients with cancer have good response to immunotherapy 11 .…”

Section: Introductionmentioning

confidence: 99%

Exploration of the role of tumor mutation burden in clinical significance, immunotherapy response predictor and immune cell infiltration in colon cancer

Xu¹,

Qu²,

Guo³

et al. 2020

Preprint

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Backgroud:Tumor mutation burden has become a powerful bio-marker to predict prognosis and immunotherapy responsiveness to patients in various cancers, but the role of TMB in colon cancer is still unclear.Methods:The transcriptome profiling data of colon patients and the simple nucleotide variation data of colon cases were downloaded from the Cancer Genome Atlas (TCGA) database. The groups were divided into high TMB and low TMB group according to the median of TMB. Then we explored the relationship between immune checkpoints, immune cells and TMB, respectively. Results: Mutation profiles of 399 colon cancer samples were analyzed in TCGA database. The senior (age＞65) had a strong relationship with higher-TMB level(p=0.001). Low-TMB group correlated with advanced N stage (P＜0.001), M stage (P＜0.001), and pathologic stage(P＜0.001). High-TMB group had significantly higher mRNA level of PD-L1, TIGIT, HAVCR2, and LAG3 than low-TMB group, which indicated high-TMB referred to better immunotherapy responsiveness in colon cancer. And high-TMB level correlated with higher fractions of CD8T cells (p=0.021), higher CD4 memory T cells(p=0.039), follicular helper T cells (p=0.002)and M1 macrophages (p＜0.001), while the low-TMB groups correlated with higher regulator T cells (p=0.002). So high-TMB correlated with stronger immune cell infiltrationConclusions:The high TMB referred to better clinical pathologic features, better immunotherapy responsiveness and stronger immune cells infiltration in colon cancer. Hence TMB may be a very promising bio-marker to predict prognosis and immunotherapy responsiveness to patients in colon cancer.

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The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity

Cited by 225 publications

References 50 publications

ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer

A Potential Biomarker of Combination of Tumor Mutation Burden and Copy Number Alteration for Efficacy of Immunotherapy in KRAS-Mutant Advanced Lung Adenocarcinoma

Exploration of the role of tumor mutation burden in clinical significance, immunotherapy response predictor and immune cell infiltration in colon cancer

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