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Zhong-Yi Dong
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OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)
- Event: WCLC 2020
- Type: Oral
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 2
- Moderators:
- Coordinates: 1/30/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA07.04 - LKB1 Deficiency Leads to an “Adenosine-Rich” Tumor Microenvironment by Recruiting Myeloid-Derived Suppressive Cells (ID 3692)
10:30 - 11:30 | Author(s): Zhong-Yi Dong
- Abstract
- Presentation
Introduction
LKB1 deficiency leads to the formation of cold tumor immune microenvironment (TME) and primary resistance to ICIs in lung adenocarcinoma. But specific molecular mechanisms are still incompletely understood. The hub role of LKB1 lies in the ability to control cell metabolism. Therefore, tackling vulnerabilities concerning immuno-metabolism probably is the breakthrough to reshape microenvironment and restore anti-tumor immunity.
Methods
Short hairpin RNAs targeting Lkb1 were utilized to generate mouse Lewis lung cancer cells with Lkb1 knockdown (LLC1-shLkb1). Mice were subcutaneously injected with LLC1-shLkb1 or LLC1 shcontrol cells, and tumor samples were harvested and analyzed for purine metabolites. Tumor-infiltrating immune cells were isolated and flow cytometry analyses were performed to investigate the impact of LKB1 alteration on the immune profiles as well as ENTPD/CD39 and NT5E/CD73 regulation. We furtherly investigated the molecular mechanisms through a series of in-vitro studies (cell culture under hypoxic conditions, western blotting, ELISA, in-vitro cell co-culture).
Results
Conclusion
Here we found that LKB1 deficiency led to accumulation of immunosuppressive adenosine in the TME, which might be the key to primary immunotherapy resistance. Furtherly, this cold TME was characterized with a contexture of polymorphonuclear myeloid derived suppressive cells (PMN-MDSCs) dominant and paucity of all the other immune cells. Interestingly, CD39 and CD73, which can catalyze ATP into adenosine, were upregulated on PMN-MDSCs in LKB1-deficient tumors. Mechanistically, deficient LKB1 dramatically induces HIF1A expression, promoting the formation of a “hypoxic” microenvironment, resulting in the recruitment of more PMN-MDSCs with high CD39 and CD73 expression. Adenosine accumulation exerted a suppressive effect on immune surveillance.
LKB1 deficiency leads to the formation of an “adenosine rich” suppressive TME, and PMN-MDSCs become the dominant source of adenosine due to higher expression of CD39 and CD73. Tailored blockade of this immuno-metabolism vulnerabilities by inhibiting adenosine production might be the breakthrough to reverse this cold environment and reinvigorate anti-tumor immunity.
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OA07.07 - PARP1 Inhibitors Enhanced IFNγ-Induced PD-L1 Expression in LKB1-Mutant Lung Cancer (ID 3642)
10:30 - 11:30 | Author(s): Zhong-Yi Dong
- Abstract
- Presentation
Introduction
STK11/LKB1 mutations define a molecular subtype of lung adenocarcinoma with a distinct T cell-excluded tumor immune microenvironment and no programmed death-ligand 1 (PD-L1) expression on tumor cells, classified as type II cancers (PD-L1−/TIL−). Dissecting the underlying mechanism of tumor PD-L1 regulation might become one of the breakthroughs to reverse this “cold” state.
Methods
Mass spectrometry, co-immunoprecipitation (CO-IP), western blotting and flow cytometry were performed in human isogenic LKB1-deficient cells transfected with lentivirus of LKB1 wild type (LV-WT), LKB1 kinase dead mutation (LV-KD) or vehicle (LV-control) (A549, H460 cell lines). Synergistic mice were grafted with LLC1-shLkb1 cells and administered with PARP1 inhibitors or Vehicle control. Subsequent flow cytometry and immunohistochemical assay were performed.
Results
Conclusion
IFN-γ-induced expression of PD-L1 was impaired in LKB1-loss and LKB1-mutant groups (A549-LV-control and A549-LV-KD), and the key vulnerability lies in decreased phosphorylated STAT1 expression and its transcriptional activity. Mass spectrometry (MS) and subsequent CO-IP showed that LKB1 interacted with PARP1 and decreased the catalytic activity of PARP1. Upon IFNγ simulation, PARP1 poly (ADP-ribosyl)ated STAT1 and subsequently inhibited STAT1 phosphorylation, which thereby impaired PD-L1 expression in LKB1 deficient cells. However, PARP1 knockdown or inhibitors decreased poly (ADP-ribosyl)ation of STAT1 and enhanced its phosphorylated level, thus increased the expression of PD-L1, in an IFNγ dependent manner. Administering PARP1 inhibitors in synergistic mouse models (LLC-shLkb1) slowed tumor growth and induced a favorable immune microenvironment by upregulating PD-L1 expression on tumor cells and increasing infiltration of CD8+ T cells.
Our research revealed that PARP1-mediated poly (ADP-ribosyl)ation of STAT1 as the key step in obstructing IFNγ-induced transcription of PD-L1 in LKB1 deficient cells. PARP1 inhibitors can specifically reverse this abnormal state, both in vitro and in vivo. These findings might provide rationales for the combination of PARP inhibitors and anti-PD-1 antibodies in LKB1 mutant lung cancer patients.
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P16 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Translational) (ID 155)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P16.04 - CDK4/6 Inhibitors Reverse Resistance to Anti-PD-1 Therapy in Lung Adenocarcinoma with LKB1 Deficiency Through pRB-ICAM1 Dependent Signaling (ID 1265)
00:00 - 00:00 | Presenting Author(s): Zhong-Yi Dong
- Abstract
Introduction
LKB1 deficiency is reported to lead to primary resistance to immune checkpoint inhibitors (ICIs) in lung adenocarcinoma. But specific molecular mechanism behind it is still incompletely understood and probably is the breakthrough to reshape microenvironment and restore anti-tumor immunity.
Methods
Tumor-Infiltrating Immune Cell Isolation and FACS Analysis were used to investigate the impact of LKB1 alteration on the immune profiles of tumor microenvironment. Then we investigated the mechanisms underlying primary resistance to ICIs through a series of invitro-studies (mRNA sequencing, mass spectrometry, Western blotting, co-immunoprecipitation, etc.). Finally, we validated our findings in syngeneic mouse models in a treatment setting.
Results
We found that LKB1 alteration (including loss and mutation) could significantly affect the whole tumor immune landscape and caused the “immune-desert” microenvironment, which was significantly associated with the expression of intercellular adhesion molecule-1 (ICAM1). ICAM1 influenced cytotoxicity of CTLs , and its expression on cancer cells was positively linked to CD8+ T cells infiltration into lung cancer tissue, indicating that ICAM1 was the core effector downstream LKB1. Mechanistic studies indicated that LKB1 hindered the interaction between cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (Rb), inhibiting the phosphorylation of Rb, which thereby lead to active transcription of ICAM1. Ultimately, we found that CDK4/6 inhibitors (Palbociclib) and PD-1 antibody combination strategy could yield therapeutic benefits with slower tumor growth and longer survival in our mouse model (figure 1), associated with a T cell and NK cell inflamed and activated immune microenvironment, through an ICAM1-dependent way (figure 2).
Conclusion
LKB1/STK11 deficiency could lead to a primary resistance to ICIs through the induction of “immune-desert” microenvironment in an pRB-ICAM1 dependent way. And an effective combination strategy of using CDK4/6 inhibitors and PD-1 antibody could reverse the resistant state, which may guide future clinical practice in lung adenocarcinoma.
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P75 - Immunotherapy (Phase II/III Trials) - Misc. Topics (ID 248)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P75.05 - Integrative Modeling of Tumor Burden and Metastatic Pattern for Second-Line anti-PD-L1 Therapy of Non–Small Cell Lung Cancer (ID 3217)
00:00 - 00:00 | Author(s): Zhong-Yi Dong
- Abstract
Introduction
Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC) in the second-line setting. However, the response to ICB therapy among patients is still heterogeneous in clinical practice.
Methods
We retrospectively assessed the impact of baseline sum of the longest diameters (SLD), number of metastatic sites and specific organ metastases on the efficacy of atezolizumab versus docetaxel in the pooled population from OAK and POPLAR studies. Then, an assistant decision model based on machine learning, incorporating these indicators, termed DSO (Diameter-Site-Organ), was developed and validated in OAK and POPLAR cohorts.
Results
Higher SLD, with the threshold of 38mm, and more metastatic sites (≥ 2) were characterized with pronounced OS benefits derived from atezolizumab versus docetaxel (Figure 1A-C). Specifically, with a systematical analysis of metastatic organs for response, brain and adrenal gland metastases were identified as favorable predictors of atezolizumab treatment (Figure 1D). The DSO decision model for guiding second-line treatment was developed based on SLD and metastatic sites and organs in the discovery cohort (Figure 2A). Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score (Figure 2B). For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0 (Figure 2C). Equivalent findings were also seen in the internal and external validation cohorts (Figure 2).
Conclusion
Our study for the first time revealed that patients with higher tumor burden were more suitable for ICB compared with standard chemotherapy. More importantly, the integrative DSO decision model might provide promising medication guidance for second-line ICB treatment in unselected NSCLC patients, and offer a research framework for frist-line regimens.
