The innate immune sensing pathways play critical roles in the defense against pathogen infection, but their roles in cancer immunosurveillance and cancer therapies are less defined. We propose that ...defective innate immune sensing inside the tumor microenvironment might limit T-cell responses to immunotherapy. A recent mechanistic understanding of conventional therapies revealed that both innate immune sensing and T-cell responses are essential for optimal antitumor efficacy. T-cell-based immunotherapy, particularly immune checkpoint blockade, has achieved great success in reactivating antitumor immune responses to lead to tumor regression, but only in a small fraction of patients. Therefore, incorporating conventional therapy that can increase innate sensing and immunotherapy should lead to promising strategies for cancer patients. Here, we review the innate sensing pathways related to cancer initiation/progression and therapies, summarize the recent key findings in innate immune sensing related to conventional therapies, evaluate current combination strategies, and highlight the potential issues of combinational therapies in terms of antitumor efficacy and toxicities.
β-Catenin regulates tumor-derived PD-L1 Han, Chuanhui; Fu, Yang-Xin
The Journal of experimental medicine,
11/2020, Letnik:
217, Številka:
11
Journal Article
Recenzirano
Odprti dostop
In this issue of JEM, Du et al. (https://doi.org/10.1084/jem.20191115) report that enhancement of the β-catenin signaling by Wnt or EGF treatment increases the expression of PD-L1 in an AKT and ...β-catenin-dependent manner, and blocking the AKT pathway synergizes with anti-PD-1 in a glioblastoma model.
High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is ...rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9
tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.
Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the ...mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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•dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β•Knockout of cGAS or STING in dMLH tumor cells renders resistance to checkpoint blockade•Downregulating cGAS-STING in human dMLH1 cancers impairs checkpoint blockade therapy
About 50% of patients with dMMR cancers are objectively responsive to immunotherapy. In addition to neoantigens, Lu et al. find that dMMR-mediated cytosolic DNA sensing by cGAS-STING pathway in tumor cells contributes to such clinical benefits, while impaired expression of cGAS-STING pathway is associated with drug resistance.
Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has ...emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1
tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.
Recently, immune checkpoint blockade (ICB), especially anti-programmed death 1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) therapy, has become an increasingly appealing therapeutic ...strategy for cancer patients. However, only a small portion of patients responds to anti-PD treatment. Therefore, treatment strategies are urgently needed to reverse the ICB-resistant tumor microenvironment (TME). It has become clear that the TME has diminished innate sensing that is critical to activate adaptive immunity. In addition, tumor cells upregulate various immunosuppressive factors to diminish the immune response and resist immunotherapy. In this review, we briefly update the current small molecular drugs that could synergize with immunotherapy, especially anti-PD therapy. We will discuss the modes of action by those drugs including inducing innate sensing and limiting immunosuppressive factors in the TME.
Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells. Here, we show that treatment with a telomere-targeting drug, 6-thio-2′-deoxyguanosine ...(6-thio-dG), leads to tumor regression through innate and adaptive immune-dependent responses in syngeneic and humanized mouse models of telomerase-expressing cancers. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/interferon I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8+ T cell activation. Moreover, 6-thio-dG overcomes resistance to checkpoint blockade in advanced cancer models. Our results unveil how telomere stress increases innate sensing and adaptive anti-tumor immunity and provide strong rationales for combining telomere-targeting therapy with immunotherapy.
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•6-thio-dG induces telomere-associated DNA damage in telomerase-positive tumor cells•6-thio-dG reduces tumor burden in T cell-dependent manner in syngeneic tumor models•Host STING signaling is required for 6-thio-dG-mediated anti-tumor effects•6-thio-dG overcomes PD-L1 blockade resistance in advanced tumors
Mender et al. show that cancer cells treated with the nucleoside analog 6-thio-2′-deoxyguanosine (6-thio-dG) undergo telomere stress and release DNA that is sensed by dendritic cells via STING-interferon signaling, which in turn activates CD8+ T cells. 6-thio-dG synergizes with immune checkpoint inhibitors.
Current predictors are largely unsatisfied for early recurrence (ER) of hepatocellular carcinoma (HCC) after thermal ablation. We aimed to explore the prognostic value of peripheral immune factors ...(PIFs) for better ER prediction of HCC after thermal ablation.
Patients who received peripheral blood mononuclear cells (PBMCs) tests before thermal ablation were included. Clinical parameters and 18 PIFs were selected to construct Model
Clin
, Model
PIFs
and the hybrid Model
PIFs-Clin
. Model performances were evaluated using area under the curve (AUC), and recurrence-free survival (RFS) were analyzed by Kaplan-Meier analysis and log-rank tests.
244 patients were included and were randomly divided in 3:1 ratio to discovery and validation cohorts. Clinical parameters including tumor size and AFP, and PIFs including neutrophils, platelets, CD3
+
CD16
+
CD56
+
NKT and CD8
+
CD28
-
T lymphocytes were selected. The Model
PIFs-Clin
showed increase in predictive performance compared with Model
Clin
, with the AUC improved from 0.664 (95%CI:0.588-0.740) to 0.801 (95%CI:0.734-0.867) in discovery cohort (p < 0.0001), and from 0.645 (95%CI:0.510-0.781) to 0.737(95%CI:0.608-0.865) in validation cohort (p = 0.1006). Model
PIFs-Clin
enabled ER risk stratification of patients. Patients predicted in Model
PIFs-Clin
high-risk subgroup had a poor RFS compared with those predicted as Model
PIFs-Clin
low-risk subgroup, with the median RFS was 18.00 month versus 100.78 month in discovery cohort (p
< 0.0001); and 24.00 month versus 60.35 month in validation cohort (p
= 0.288). Patients in different risk subgroups exhibited distinct peripheral immune contexture.
Peripheral immune cells aiding clinical parameters boosted the prediction ability for ER of HCC after thermal ablation, which be helpful for pre-ablation ER risk stratification.
Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. ...However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.
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