Anti–PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC

Tu, Eric; McGlinchey, Kelly; Wang, Jixin; Martin, Philip; Ching, Steven; Floc’h, Nicolas; Kurasawa, James; Starrett, Jacqueline H.; Lazdun, Yelena; Wetzel, Leslie; Nuttall, Barrett; Ng, Felicia S.L.; Coffman, Karen; Smith, Paul D.; Politi, Katerina; Cooper, Zachary A.; Streicher, Katie

doi:10.1172/jci.insight.142843

Cited by 62 publications

(49 citation statements)

References 54 publications

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“…Analysis of all common sequence (447 genes) and chromosomal (genome-wide) variants was notable for a significant positive correlation between CD73 protein expression (by IHC) and EGFR amplification (p = 0.029) (Fig. 5B), consistent with the link we identified between CD73 expression and the EGFR-associated AC-like state in scRNA-seq data from adult glioblastoma as well as reports of EGFR-mutated NSCLC expressing higher levels of CD73 compared with EGFR wild-type tumors 59,60 . In a large independent cohort of glioblastoma from the TCGA, we also found a statistically significant positive correlation between EGFR and CD73 expression (p = 0.039).…”

Section: Cd73 Expression Correlates With Oncogenic Signaling and Clin...supporting

confidence: 86%

“…Nevertheless, glioblastoma tumor growth was reduced in CD73-null mice with combined inhibition of CTLA-4 and PD-1 checkpoints 34 suggesting a potential benefit of combined inhibition of extracellular purinergic pathway and checkpoint pathways. A similar benefit of combined anti-CD73/anti-PD1 therapy has been observed in models of EGFR-mutated NSCLC 59 , and early-stage clinical trials 57,58 , suggesting that CD73 inhibition may provide additional complementary or synergistic therapeutic benefits with other immunotherapies.…”

Section: Discussionsupporting

confidence: 54%

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Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

et al. 2022

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How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

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Section: Cd73 Expression Correlates With Oncogenic Signaling and Clin...supporting

confidence: 86%

Section: Discussionsupporting

confidence: 54%

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

et al. 2022

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“…Further, lower CD8 + TIL levels were related to EGFR mutation. EGFR mutations can upregulate CD73 expression, increase Treg numbers, and stimulate conversion of ATP into immunosuppressive adenosine, contributing to cancer progression and metastasis [ 8 , 84 , 85 ]. Increased activation of Tregs mediated by adenosine and accumulation of MDSCs, along with lower anticancer activities of natural killer cells and DCs, increased macrophage polarization toward the M2-phenotype, and inhibition of the effector T-cell-mediated response collectively led to tumor immune escape [ 86 ].…”

Section: Role Of Tme In Lung Cancer Evolution and Prognosismentioning

confidence: 99%

“…Consistently, the authors observed an increase in expression levels of genes involved in inflammation and T-cell function in tumors treated with a combination of anti-PD-L1 and anti-CD73 antibodies. These results indicate that a combination of anti-CD73 and anti-PD-L1 therapies may be effective in treating EGFR-mutated NSCLC [ 84 ].…”

Section: Role Of Tme In Lung Cancer Evolution and Prognosismentioning

confidence: 99%

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

Madeddu

Donisi

Liscia

et al. 2022

IJMS

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Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development.

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“…However, induction of counter-regulatory factors such as CD73, which generates the immunosuppressive metabolite adenosine, may suppress tumor immunogenicity (22), particularly in EGFR-mutated NSCLC (23,24). Human CD73 is encoded by NT5E, which is located on the long arm (q) of chromosome 6.…”

Section: Introductionmentioning

confidence: 99%

MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer

et al. 2022

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Immunotherapy has shown limited efficacy in EGFR-mutated lung cancer patients. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity. However, STING activation was restrained by the ectonucleosidase CD73, which is induced in MET-amplified, EGFR TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on co-induction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI resistant EGFR-mutated lung cancers and promote immunogenicity.

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Anti–PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC

Cited by 62 publications

References 54 publications

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer

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