PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR

Ghosh, Soma; Nataraj, Nishanth Belugali; Noronha, Ashish; Patkar, Sushant; Sekar, Arunachalam; Mukherjee, Saptaparna; Winograd‐Katz, Sabina; Kramarski, Lior; Verma, Aakanksha; Lindzen, Moshit; Drago-García, Diana; Green, Joseph; Eisenberg, Galit; Gil-Henn, Hava; Basu, Arkaprabha; Lender, Yan; Weiss, Shimon; Oren, Moshe; Lotem, Michal; Geiger, Benjamin; Ruppin, Eytan; Yarden, Yosef

doi:10.1016/j.celrep.2021.109181

Cited by 30 publications

(24 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…in ALK- or EGFR-driven lung cancer 54 , 55 , where ICB may even be related with severely increased adverse event rates in certain scenarios 56 . In accordance with previous reports, PD-L1 expression depended upon EGFR activity 57 and PD-1/EGFR inhibitor combination could not prevent tumor outgrowth in our humanized PDX models. At the same time, we observed an upregulation of alternative immune checkpoints such as VTCN1 (B7-H4), which has been associated with limited ICB response and reduced T-cell activity previously 41 , 58 .…”

Section: Discussionsupporting

confidence: 93%

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

et al. 2021

View full text Add to dashboard Cite

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.

show abstract

Section: Discussionsupporting

confidence: 93%

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

et al. 2021

View full text Add to dashboard Cite

show abstract

“…As mentioned previously, patients suffering from Non-Small Cell Lung Cancer (NSCLC) with EGFR mutations had strikingly poor responses to PD-1 based immunotherapies compared to those with wt EGFR [ 29 , 30 , 31 ]. This came as a surprise given that numerous in vitro and in vivo studies had previously identified EGFR-mediated signalling as a driver for the upregulation of PD-L1 expression on tumour cells [ 32 , 33 , 34 , 36 ] and solid tumours with high PD-L1 expression were expected to be likely responders of PD-L1/PD-1 immunotherapies [ 3 ]. Furthermore, immunohistochemistry analyses in multiple studies have highlighted an increased expression of PD-L1 in patients who have NSCLC adenocarcinomas expressing mutated forms of the EGFR [ 38 , 39 ].…”

Section: The Role Of Egfr In Immune Suppression: Egfr Mutations and The Lymphocyte Depletion Phenotypementioning

confidence: 99%

“…Furthermore, in a second line of argumentation, it was observed that patients overexpressing mutant forms of the EGFR showed exceptionally low clinical efficacy following the treatment with ICIs, as compared to patients expressing wt EGFR [ 29 , 30 , 31 ]. Given that EGFR-mediated signalling has been established to upregulate PD-L1 expression on tumour cells [ 32 , 33 , 34 , 35 , 36 ], it had originally been hypothesized that the treatment landscape for such cancers could be revolutionized by CD8 T-cell enhancing immunotherapies like PD-L1 inhibitors [ 11 ]. However, for reasons that remain largely unelucidated, EGFR overexpressing tumours instead remain resistant to such treatments [ 29 , 30 , 31 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given that EGFR-mediated signalling has been established to upregulate PD-L1 expression on tumour cells [ 32 , 33 , 34 , 35 , 36 ], it had originally been hypothesized that the treatment landscape for such cancers could be revolutionized by CD8 T-cell enhancing immunotherapies like PD-L1 inhibitors [ 11 ]. However, for reasons that remain largely unelucidated, EGFR overexpressing tumours instead remain resistant to such treatments [ 29 , 30 , 31 , 36 ]. Interestingly, a recent publication revealed a direct, positive correlation between EGFR mutation status and a so called “lymphocyte depletion” phenotype of these tumours, in which there was a pronounced lack of tumor-infiltrating CD8 T-cells [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Emerging Role of EGFR Mutations in Creating an Immune Suppressive Tumour Microenvironment

Kapoor

Zaiss

2021

Biomedicines

View full text Add to dashboard Cite

Several types of tumours overexpress the Epidermal Growth Factor Receptor (EGFR) in either wild type or mutated form. These tumours are often highly aggressive and difficult to treat. The underlying mechanisms for this phenomenon have remained largely unresolved, but recent publications suggest two independent mechanisms that may contribute. According to one line of research, tumours that overexpress the EGFR grow autonomously and become “addicted” to growth factor signalling. Inhibition of this signal using EGFR inhibitors can, therefore, induce cell death in tumour cells and lead to tumour shrinkage. The other line of research, as highlighted by recent findings, suggests that the overexpression, specifically of mutant forms of the EGFR, may create an immune-suppressive and lymphocyte depleted microenvironment within tumours. Such a lymphocyte depleted microenvironment may explain the resistance of EGFR overexpressing cancers to tumour therapies, particularly to check-point inhibitor treatments. In this article, we discuss the recent data which support an immune modulatory effect of EGFR signalling and compare these published studies with the most recent data from The Cancer Genome Atlas (TCGA), in this way, dissecting possible underlying mechanisms. We thereby focus our study on how EGFR overexpression may lead to the local activation of TGFβ, and hence to an immune suppressive environment. Consequently, we define a novel concept of how the mitogenic and immune modulatory effects of EGFR overexpression may contribute to tumour resistance to immunotherapy, and how EGFR specific inhibitors could be used best to enhance the efficacy of tumour therapy.

show abstract

“…29 The metastasis, invasion and proliferation of tumor cells are regulated by fibrinogen via binding to growth factors, eg, PDGF (platelet-derived growth factor), FGF-2 (fibroblast growth factor-2), and VEGF (vascular endothelial growth factor). [30][31][32] Tumor progression is shown to be related to inflammatory response, that's, leukocyte infiltration in the tumor matrix, and fibrinogen is converted to fibrin, thereby promoting tumor angiogenesis. 33 Also, EMT (epithelialmesenchymal transition) of tumor cells is facilitated by fibrinogen, which also promotes tumor metastasis and invasion.…”

mentioning

confidence: 99%

Early Prediction of Objective Response of Fibrinogen in a Real-World Cohort of Hepatocellular Carcinoma Cases Treated by Programmed Cell Death Receptor-1 and Lenvatinib

Shen¹,

Wang²,

Wei³

et al. 2021

OTT

View full text Add to dashboard Cite

Background: This cohort study aimed to investigate the influence of fibrinogen on progressionfree survival and overall survival in unresectable HCC cases treated by PD-1 and lenvatinib. Methods: A total of 57 unresectable HCC cases who received lenvatinib and PD-1, such as toripalimab, camrelizumab, or sintilimab, in Beijing Ditan Hospital Affiliated to Capital Medical University were enrolled in this study. Results: Vascular invasion, high FIB (>2.83g/L), and metastasis were highly correlated with low PFS. There was a significant correlation between a raised risk of death and metastasis and increased FIB (>2.83g/L). Conclusion: FIB is associated with outcomes of unresectable HCC cases treated by PD-1 and lenvatinib.

show abstract

PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR

Cited by 30 publications

References 65 publications

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Emerging Role of EGFR Mutations in Creating an Immune Suppressive Tumour Microenvironment

Early Prediction of Objective Response of Fibrinogen in a Real-World Cohort of Hepatocellular Carcinoma Cases Treated by Programmed Cell Death Receptor-1 and Lenvatinib

Contact Info

Product

Resources

About