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D.L. Gibbons



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    MINI 27 - Biology and Other Issues in SCLC (ID 152)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MINI27.10 - Discussant for MINI27.06, MINI27.07, MINI27.08, MINI27.09 (ID 3380)

      17:35 - 17:45  |  Author(s): D.L. Gibbons

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 13 - Immunotherapy Biomarkers (ID 104)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL13.07 - EMT Is Associated with an Inflammatory Tumor Microenvironment with Elevation of Immune Checkpoints and Suppressive Cytokines in Lung Cancer (ID 2134)

      17:50 - 18:01  |  Author(s): D.L. Gibbons

      • Abstract
      • Presentation
      • Slides

      Background:
      Promising results in the treatment of NSCLC have been seen with immunomodulatory agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. Epithelial-mesenchymal transition (EMT) is a key process driving metastasis and drug resistance. Previously we have developed a robust EMT gene signature, highlighting differential patterns of drug responsiveness for epithelial and mesenchymal tumor cells.

      Methods:
      We conducted an integrated analysis of gene expression profiling from three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung and two large datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry, in vivo mouse models and correlation with clinical data were performed.

      Results:
      EMT is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, along with increases in tumor infiltration by CD4+Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Similarly, IL-6 and indoleamine 2, 3-dioxygenase (IDO) were elevated in these tumors. We demonstrate that in murine models of lung adenocarcinoma, many of these changes are recapitulated by modulation of the miR-200/ZEB1 axis, a known regulator of EMT. Furthermore, B7-H3 is found to negatively correlate with overall survival and recurrence free survival, indicating a potential new therapeutic target in lung adenocarcinoma in the future.

      Conclusion:
      EMT, commonly related to cancer metastasis and drug resistance, is highly associated with an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoints and that is regulated at least in part by the miR-200/ZEB1 axis. These findings suggest that EMT may have potential utility as a biomarker selecting patients more likely to benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers.

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    ORAL 21 - Biology - Moving Beyond the Oncogene to Oncogene-Modifying Genes (ID 118)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL21.02 - Landscape and Functional Significance of KRAS Co-Mutations in Lung Adenocarcinoma (LUAC) (ID 3224)

      10:56 - 11:07  |  Author(s): D.L. Gibbons

      • Abstract
      • Presentation
      • Slides

      Background:
      The biological heterogeneity of KRAS-mutant LUAC represents a major impediment to the successful implementation of targeted therapeutic strategies for this clinically challenging group of lung cancer patients. Through integrative, multi-platform analysis of large scale omics data we recently identified three major subsets of KRAS-mutant LUAC defined on the basis of co-occurring genomic alterations in STK11/LKB1 (KL subgroup), TP53 (KP) and CDKN2A/B (KC), the latter coupled with low expression of the TTF1 transcription factor. We further demonstrated subset-specific molecular dependencies, patterns of immune system engagement and therapeutic vulnerabilities. Here, we extend these findings through comprehensive analysis of a wide panel of KRAS co-mutations and assess the impact of key co-mutations on facets of the malignant phenotype including flux through the MAPK and PI3K/AKT pathways and heterotypic interactions with the host immune system.

      Methods:
      Our datasets consisted of 431 tumors from TCGA (122 KRAS-mutant), 41 additional chemo-naive KRAS-mutant LUACs (PROSPECT dataset) and 36 platinum-refractory KRAS-mutant LUACs from the BATTLE-2 clinical trial. Significant KRAS co-mutations were identified on the basis of a P value threshold of ≤0.05 (Fisher’s exact test) coupled with a baseline prevalence of ≥3%. RNASeq data were downloaded directly from the TCGA site. Expression profiling of PROSPECT tumors was performed using the Illumina Human WG-6 v3 BeadChip Array whereas BATTLE-2 tumors were profiled using the GeneChipâHuman Gene 1.0 ST Array from Affymetrix. Generation of MAPK and PI3K proteomic scores, based on Reverse Phase Protein Array (RPPA) data, has been previously reported.

      Results:
      Our analysis identified somatic mutations in 31 genes as significantly co-mutated with KRAS in LUAC samples. Among them, co-mutations in STK11/LKB1 (P=0.00011) and ATM (P=0.0004) predominated. Somatic mutations in ERBB4 (P=0.0059), encoding a member of the ErbB family of receptor tyrosine kinases and MAP3K4 (P=0.0017) were also enriched in KRAS-mutant LUAC. We assessed the impact of KRAS co-mutations on the amplitude and directionality of signaling downstream of mutant KRAS using the proteomic “MAPK score“ and “PI3K score” as surrogates of effector pathway activation. Interestingly, co-mutations in ERBB4 were associated with significantly suppressed flux through the MAPK pathway (P=0.0024, t-test). Somatic mutations in other genes, including CAMSAP2, were associated with suppressed signaling through both the MAPK (P=0.00876, t-test) and PI3K-AKT (P=0.0032, t-test) cascades. Finally, within KRAS-mutant tumors, co-mutations in NLRC5, a master transcriptional regulator of MHC Class I molecules were associated with reduced mRNA expression of several of its classical target genes. In addition, low mRNA expression of NLRC5 correlated strongly with reduced expression of key components of the antigen presentation pathway across multiple independent datasets of chemotherapy naïve and platinum refractory KRAS-mutant tumors and cell lines. Thus, in addition to cell autonomous effects, co-mutations can also impinge on the reciprocal relationship between malignant cells and their immune microenvironment.

      Conclusion:
      Our work identifies a compendium of KRAS co-mutations that impact classical and emerging cancer hallmarks, including evasion of the host immune response. Systematic interrogation of the functional impact of prevalent KRAS co-mutations is essential for the development of personalized treatment approaches for this heterogeneous group of tumors.

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    P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P2.04-066 - Programmed Cell Death Ligand 1 (PD-L1) Overexpression and Low Immune Infiltrate Score Correlate with Poor Outcome in Lung Adenocarcinoma (ID 776)

      09:30 - 09:30  |  Author(s): D.L. Gibbons

      • Abstract

      Background:
      PD-L1 is a key immunoregulatory checkpoint which suppresses cytotoxic immune response in a variety of physiologic and pathologic conditions. Thus, inhibition of PD-L1 can lead to reactivating tumor immunity and assist to cancer therapy. PD-L1 overexpression in the tumor cells has been correlated to a lessened immune response and consequent worse prognosis in a variety of cancers. To better understand the immune profiling of PD-L1 expression and its interplay with immune cells, we analyzed the correlation between image analysis-based immunohistochemical (IHC) expression of PD-L1 and tumor infiltrating immune cells density in surgically resected non-small cell lung carcinomas (NSCLC), and the correlation with clinical and pathological features, including patient outcome.

      Methods:
      IHC for PD-L1, PD-1, CD3, CD4, CD8, CD45RO, CD57, CD68, Granzyme B and FOXP3 were performed in 254 surgical resected stages I-III NSCLC, Adenocarcinoma (ADC=146) and Squamous cell Carcinoma (SqCC=108) from formalin-fixed and paraffin-embedded tissues. PD-L1 membrane expression on tumor cells and density of inflammatory cells were quantified using image analysis in intra-tumoral (IT) and peri-tumoral (PT) compartments. H-score > 5 was used as a cut-off for positive PD-L1 expression and an immune-score (IMS) using CD8/CD4/CD68 was devised. PD-L1 expression and inflammatory cells were correlated with clinico-pathologic features and patient outcomes.

      Results:
      Positive PD-L1 expression was seen in 26.84% (n=69) of the entire cohort, 23.29% (n=34) of 146 ADC and 23.40% (n=35) of 115 SqCC. In ADC, higher levels of PD-L1 expression were detected in tumors with solid histology pattern compared with other histology patterns (P=0.034), and in lifetime smokers compared with non-smokers (P<0.0001). In SqCC PD-L1 expression was positive correlation with tumor size (Rho=0.19471, P=0.0435). In overall, PD-L1 expression correlated positively with inflammatory cell density in both IT and PT compartments in ADC and SqCC. Patients with KRAS mutation (P=0.00058), solid tumor (P<0.0001) or smoker (P = 0.0446) were more likely to have positive PD-L1 expression tumor cells in ADC. No correlation was detected between EGFR mutation and immune markers. Using PD-L1 and CD8/CD4/CD68 IMS expression levels, in ADC and SqCC, we identified 4 groups of tumors (Table 1). Multivariate Cox proportional hazard regression analysis demonstrated that tumors with high PD-L1 expression and low IMS in ADC exhibited significantly poor recurrence-free (HR=4.299; P=0.0101) and overall survival (HR=5.632; P=0.0010).

      Table 1. Summary of the correlation between PD-L1 expression levels and immune-score (IMS=CD8/CD4/CD68) in adenocarcinoma (ADC) and squamous cells carcinoma (SQCC).
      PDL-1 H-score (ADC) IMS (Low) IMS (High) Total
      <5 61 (41.78%) 51 (34.93%) 112 (76.71%)
      ≥5 8 (5.48%) 26 (17.81%) 34 (23.29%)
      Total 69 (47.26%) 77 (52.74%) 146 (100.0%)
      PDL-1 H-score (SqCC)
      <5 37 (34.30%) 36 (33.30%) 73 (67.60%)
      ≥5 17 (15.70%) 18 (16.70%) 35 (32.40%)
      Total 54 (50.00%) 54 (50.00%) 108 (100.0%)


      Conclusion:
      Higher PD-L1 expression is associated with solid pattern in adenocarcinoma and higher level of tumoral immune infiltrate. We developed an immune score which when combined with PD-L1 expression significantly correlates with patient outcome in surgically resected ADCs. (Supported by grants UT-Lung SPORE P50CA70907 and CPRIT RP120713).