Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional <i>STK11</i> Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

Pore, Nabendu; Wu, Song; Standifer, Nathan; Jure-Kunkel, Maria; Reyes, Melissa de los; Shrestha, Yashaswi; Halpin, Rebecca; Rothstein, Raymond; Mulgrew, Kathy; Blackmore, Stephen; Martin, Philip; Meekin, John; Griffin, Matthew E.; Bisha, Ina; Proia, Theresa A.; Miragaia, Ricardo J.; Herbst, Ronald; Gupta, Ashok; Abdullah, Shaad E.; Raja, Rajiv; Frigault, Melanie M.; Barrett, J. Carl; Dennis, Phillip A.; Ascierto, Maria Libera; Oberst, Michael D.

doi:10.1158/2159-8290.cd-20-1543

Cited by 54 publications

(47 citation statements)

References 44 publications

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“…Genetic ablation of STK11 in a KRAS-driven murine model of NSCLC demonstrated an accumulation of neutrophils with T-cell suppressive capacities associated with a decreased number of tumor-infiltrating lymphocytes and a reduced expression of PD-L1 in tumors [74]. In an in vitro model, STK11 extinction did not substantially modify the growth of KRAS-mutant colorectal tumors [75]. Conversely, in an immunocompetent mouse model, tumor growth increased, related to a loss of immune control [75].…”

Section: Tumor-extrinsic Impact Of Stk11/lkb1 Alteration: Interaction...mentioning

confidence: 98%

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Pons‐Tostivint

Lugat

Fontenau

et al. 2021

Cells

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The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.

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Section: Tumor-extrinsic Impact Of Stk11/lkb1 Alteration: Interaction...mentioning

confidence: 98%

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Pons‐Tostivint

Lugat

Fontenau

et al. 2021

Cells

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“…The genes in the PD-L1-H group that were expressed at lower levels exhibited a negative relation with immunotherapy. CCL26, for example, has been shown to be highly expressed in recurrent hepatocellular carcinoma (HCC) ( 33 ), while CXCL2 is highly expressed in STK11-mutated NSCLC, which has a poorer response rate to ICIs ( 34 ). Notably, STK11 mutations were rarer in the PD-L1-H group than the other two groups herein.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Immunological Characteristics and Genomic Alterations in HPV-Positive Oropharyngeal Squamous Cell Carcinoma Based on PD-L1 Expression

Shi

Xia

et al. 2022

Front. Immunol.

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Programmed death-ligand 1 (PD-L1) expression has been approved as an immune checkpoint inhibitor (ICI) response predictive biomarker; however, the clinicopathological and molecular features of HPV-positive oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] based on PD-L1 expression are not well studied. We aimed to characterize clinicopathological, tumor immune microenvironmental, and molecular features of HPV(+)OPSCC with different PD-L1 expression scored by combined positive score (CPS). A total of 112 cases were collected from 2008-2021 and received PD-L1 and CD8 immunohistochemistry (IHC) staining. 71 samples received DNA sequencing out of which 32 samples received RNA sequencing for immune-related gene alterations or expression analysis. The 32 samples were also subjected to analysis of CD20, CD4, CD8, CD68, Foxp3 and P16 by multiplex immunofluorescence (mIF) staining, and the immune markers were evaluated in the tumor body (TB), tumor margin (TM) and normal stroma (NS) regions separately. Our results showed that of 112 HPV(+)OPSCC tumors, high(CPS≥20), intermediate(1≤CPS<20), and low(CPS<1) PD-L1 expression was seen in 29.5%, 43.8% and 26.8% cases respectively. Non-smoking patients and patients with tumors occurring at the tonsils or having rich lymphocytes infiltration had significantly higher PD-L1 expression. Patients with CPS≥20 had significantly higher tumor mutation burden (TMB, p=0.0058), and PD-L1 expression correlated significantly with CD8+ T cells infiltration, which were ample in tumor regions than in NS in mIF. CD20+, CD4+, CD68+, Foxp3+CD4+ cells were demonstrated to infiltrate higher in TM while CD20+ and CD68+ cells were also enriched in NS and TB regions respectively. However, none of them showed correlations with PD-L1 expression. ARID1A, STK11 alterations were enriched in the low PD-L1 group significantly, while anti-viral immune associated APOBEC mutation signature and immune-related genes expression such as XCL1 and IL11 were positively associated with PD-L1 expression (p<0.05). This is a comprehensive investigation revealing immune and molecular features of HPV(+)OPSCC based on PD-L1 expression. Our study suggested that 73.2% of HPV(+)OPSCC patients may benefit from immunotherapy, and high PD-L1 expression reflects immune-active status of HPV(+)OPSCC accompanied by higher immune effect factors such as TMB, CD8+ cytotoxic T cells and immune-related genomic alterations. Our study offers valuable information for understanding the immune features of HPV(+)OPSCC.

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“…Interestingly, IL-6 knockdown in cancer associated fibroblasts (CAF) increased IFN-γ on CD8-postive T cells and IL-6 blockade could reverse anti-PD-L1 resistance in an HCC mouse model [ 48 ]. Recently, a comprehensive study in non-small cell lung cancer demonstrated that reduction in STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout mouse models [ 49 ]. Supporting these data, inhibition of the AURKA/STAT3 signaling pathway promoted effective T-cell infiltration into the tumor microenvironment and improved anti-PD-1 efficacy [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma

Ploeger

Schreck

Huth

et al. 2022

Cancers

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Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) are key transcription factors activated by pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6 (IL-6). In this study, we combined in vitro cell culture experiments and immunohistochemical analyses of human HCC (N = 124) and CCA (N = 138) specimens. We observed that in the absence of STAT3, IL-6 induced the activation of STAT1 and its target genes suggesting that IL-6 derived from the tumor microenvironment may activate both STAT1 and STAT3 target genes in HCC tumor cells. In addition, STAT1 and STAT3 were highly activated in a subset of HCC, which exhibited a high degree of infiltrating CD8- and FOXP3-positive immune cells and PD-L1 expression. Our results demonstrate that STAT1 and STAT3 are expressed and activated in HCC and tumor infiltrating immune cells. In addition, HCC cases with high STAT1 and STAT3 expression also exhibited a high degree of immune cell infiltration, suggesting increased immunological tolerance.

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Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

Cited by 54 publications

References 44 publications

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Analysis of Immunological Characteristics and Genomic Alterations in HPV-Positive Oropharyngeal Squamous Cell Carcinoma Based on PD-L1 Expression

STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma

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