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  • 1
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    Cytokeratin-8 in Anaplastic Thyroid Carcinoma: More Than a Simple Structural Cytoskeletal Protein
    MDPI AG ; 2018
    In:  International Journal of Molecular Sciences Vol. 19, No. 2 ( 2018-02-14), p. 577-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 19, No. 2 ( 2018-02-14), p. 577-
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms19020577
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
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    Real-time polymerase chain reaction : A revolution in diagnostics
    Springer Science and Business Media LLC ; 2008
    In:  Resonance Vol. 13, No. 4 ( 2008-4), p. 369-377
    Details
    In: Resonance, Springer Science and Business Media LLC, Vol. 13, No. 4 ( 2008-4), p. 369-377
    Type of Medium: Online Resource
    ISSN: 0971-8044 , 0973-712X
    URL: Article
    DOI: 10.1007/s12045-008-0017-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2085223-X
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  • 3
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    Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 7_suppl ( 2019-03-01), p. 607-607
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 7_suppl ( 2019-03-01), p. 607-607
    Abstract: 607 Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high T eff high /PD-L1+ are more likely to respond to ICI. Here, we use this T eff gene panel as well as other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 69 pts with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing to measure transcript levels of genes related T eff status. T eff status was defined as the mRNA expression of 17 genes (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1), with T eff high/low separated at the median. PD-L1 positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay, and TMB high as 〉 10 mutations per megabase. Inflamed tumors were defined as CD8 expression in the top 75th percentile compared to a large reference population of multiple tumor types. Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, T eff gene expression, PD-L1 positive, and TMB were associated with disease control (DC, defined as CR, PR, or stable disease). DC comparisons were tested using a chi-squared test with Yates’s continuity correction. Results: DC was 63% (5/8) amongst PD-L1 positive pts and 52% (31/60) in PD-L1 negative patients (p = 0.84). Only 2 pts were TMB high. The majority of mRCC tumors (97%, 67/69) were TMB low. 6-month DC in TMB high tumors was 50% (1/2) and 49.3% (33/67) in TMB low tumors (p = 1.0). 36 pts were classified as T eff high and 33 patients were classified as T eff low . 6-month DC was 61% (22/36) in the T eff high cohort and 36% (12/33) in the T eff low cohort (p = 0.069). 6-month DC was 64% of inflamed tumors (16/25) vs 41% of non-inflamed tumors (18/44) (p = 0.111). Conclusions: TMB high and PD-L1 expression do not reliably predict for DC in pts with mRCC. Utilizing a gene signature score may better predict ICI response.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.7_suppl.607
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Effect of CTLA-4 overexpression on response to ipilimumab in melanoma.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 5_suppl ( 2018-02-10), p. 190-190
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 5_suppl ( 2018-02-10), p. 190-190
    Abstract: 190 Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r 2 = .41, p = .004). This was observed in the monotherapy group (r 2 = .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r 2 = .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.5_suppl.190
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Correlation of lung cancer mutational profile with immune profile.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 5_suppl ( 2018-02-10), p. 146-146
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 5_suppl ( 2018-02-10), p. 146-146
    Abstract: 146 Background: The association between neoplasm mutational and immune profiles has not been well-characterized. Methods: We collected 26 lung cancer formalin-fixed paraffin embedded (FFPE) samples which had been tested with a comprehensive mutation profile to detect clinically actionable mutations, and a comprehensive immune gene expression profile, which interrogates PD-L1 immunohistochemistry (IHC), PD-L1/2 copy number, CD3/CD8 IHC, microsatellite instability status, mutational burden, and the expression profile of 54 immune-related genes. The ranking of gene expression and 7 immune phenotypes was compared to a reference population. Six cases were positive for an activating KRAS mutation and 2 cases were positive for an activating EGFR mutation. Principal component analysis was performed to determine the association of EGFR/KRAS mutations with the measured immune landscape. Results: The proinflammatory immune phenotype was significantly correlated with KRAS mutation positive samples (first principal component, R squared = 0.53, p 〈 0.05). Similarly, CD38 expression was correlated with KRAS mutation (R squared = 0.47, p 〈 0.05). CD137, KLRD1, and DDX58 expression was significantly correlated with EGFR positive samples (second principal component, R squared = 0.47, 0.37, 0.35 respectively, p 〈 0.05 in all cases). Unsupervised hierarchical clustering of the samples resulted in three distinct clusters, EGFR positive, KRAS positive, and EGFR negative/KRAS negative. In the KRAS positive cluster, high proinflammatory immune phenotype, VISTA moderate expression, presence of CD3/CD8 tumor infiltrating lymphocytes (TILs), and low KLRD1 were overrepresented (p 〈 0.05), while low VISTA and proinflammatory moderate immune phenotype were significantly underrepresented (p 〈 0.05). In the EGFR positive cluster DDX58 high, very low TILs, and very low CD8 were significantly (p 〈 0.05) overrepresented. Conclusions: KRAS mutation positivity is significantly associated with a proinflammatrory immune phenotype and CD3/CD8 infiltration. KRAS positive, EGFR positive, and KRAS/EGFR negative clusters are immunophenotypically distinct. A higher number of specimens is necessary to verify and expand these findings.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.5_suppl.146
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 8_suppl ( 2019-03-10), p. 63-63
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 8_suppl ( 2019-03-10), p. 63-63
    Abstract: 63 Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high T eff high /PD-L1+ are more likely to respond to ICI. Here, we use this T eff gene panel as well as other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 69 pts with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing to measure transcript levels of genes related T eff status. T eff status was defined as the mRNA expression of 17 genes (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1), with T eff high/low separated at the median. PD-L1 positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay, and TMB high as 〉 10 mutations per megabase. Inflamed tumors were defined as CD8 expression in the top 75th percentile compared to a large reference population of multiple tumor types. Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, T eff gene expression, PD-L1 positive, and TMB were associated with disease control (DC, defined as CR, PR, or stable disease). DC comparisons were tested using a chi-squared test with Yates’s continuity correction. Results: DC was 63% (5/8) amongst PD-L1 positive pts and 52% (31/60) in PD-L1 negative patients (p = 0.84). Only 2 pts were TMB high. The majority of mRCC tumors (97%, 67/69) were TMB low. 6-month DC in TMB high tumors was 50% (1/2) and 49.3% (33/67) in TMB low tumors (p = 1.0). 36 pts were classified as T eff high and 33 patients were classified as T eff low . 6-month DC was 61% (22/36) in the T eff high cohort and 36% (12/33) in the T eff low cohort (p = 0.069). 6-month DC was 64% of inflamed tumors (16/25) vs 41% of non-inflamed tumors (18/44) (p = 0.111). Conclusions: TMB high and PD-L1 expression do not reliably predict for DC in pts with mRCC. Utilizing a gene signature score may better predict ICI response.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.8_suppl.63
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Cell proliferation as a biomarker for response to immune checkpoint inhibitors in highly inflamed renal cell carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 8_suppl ( 2019-03-10), p. 61-61
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 8_suppl ( 2019-03-10), p. 61-61
    Abstract: 61 Background: Cell proliferation is an important marker of survival in many tumors and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors in RCC. Previously we reported (SITC 2018) moderately proliferative lung cancer has a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE tumor samples of RCC were evaluated by RNA-seq to measure transcript levels of 394 immune related genes, including 10 related to cell proliferation (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A). Cell proliferation, defined as the mean mRNA expression of these 10 genes was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( 〈 33), moderately (33-66) and highly ( 〉 66) proliferative compared to a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. Tumors were inflamed or non-inflamed based upon RNA‐seq analysis of CD8 compared to a reference population of more than 500 cases of multiple tumors. Non-inflamed, or immune desert tumors, defined as the lower 25 th percentile of rank for CD8 + T-cells, and greater than 75 th percentile of rank as inflamed. Results: In our cohort of 69 patient the overall ORR was 18.8%. 15.9% of tumors were non-inflamed with an ORR of 9.1%. For 36.2% inflamed tumor the ORR was 32%. For cell proliferation 62.2% were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately. ORR in moderately proliferative tumors was 30% versus 14.2% in poorly/highly proliferative tumors. In inflamed tumors, ORR in moderately proliferative tumors was 37.5% as opposed to 17.6% in poorly/highly proliferative tumors. In 11 non-inflamed tumors, there was only one responder, which was a poorly/highly proliferative tumor. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of inflamed tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.8_suppl.61
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 8
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    Immune profiling and immunotherapeutic targets in pancreatic cancer
    AME Publishing Company ; 2021
    In:  Annals of Translational Medicine Vol. 9, No. 2 ( 2021-1), p. 119-119
    Details
    In: Annals of Translational Medicine, AME Publishing Company, Vol. 9, No. 2 ( 2021-1), p. 119-119
    Type of Medium: Online Resource
    ISSN: 2305-5839 , 2305-5847
    URL: Journal
    URL: Article
    DOI: 10.21037/atm
    DOI: 10.21037/atm-20-1076
    Language: Unknown
    Publisher: AME Publishing Company
    Publication Date: 2021
    detail.hit.zdb_id: 2893931-1
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  • 9
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    Abstract 620: Tumor microenvironment heterogeneity is not identified across multiple histologically similar tumors from the same patient
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 620-620
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 620-620
    Abstract: Introduction: Tumor heterogeneity has been well documented for mutational analysis in virtually all types of tumors and is accepted as a true finding. Heterogeneity of the tumor microenvironment (TME) in the context of response to checkpoint inhibitors has not been well studied; the belief is that variation will be identified across multiple tumors from the same patient. The expectation is that multiple tumors from a single patient would demonstrate extensive TME heterogeneity driven by the neoplasm. Methods: We validated and utilized a targeted RNA-seq immune panel of & gt;350 genes to interrogate the TME of 49 different tumors from 17 unique patients. These samples for one patient represented primary and metastatic tumors that were separated by multiple years. Prior to this study we built a reference database of RNA-seq immune results for this panel of 167 samples. An in-depth analysis of genes associated with checkpoint inhibition (CPI) and tumor infiltrating lymphocytes (TILs) were the focus of the comparative analysis. Unsupervised analysis and gene rank by RNA-seq were the primary modes of comparison. Results: For more than one-half of these patients the different tumors for a single patient separated by multiple years more closely resembled the other tumors from that patient than the reference population by unsupervised clustering. When ranked by LOW, MODERATE, or HIGH expression of genes associated with TILs or CPI the results for the majority of patients were highly concordant: LOW TILs / LOW CPI associated gene expression. Conclusion: Our results support a paradigm shift in the influence of the host on TME heterogeneity with evidence that the host and not the neoplastic cells are the primary determining factor. TME heterogeneity is not identified across multiple tumors of the same histology collected from different sites across time points from the same patient. This study does not evaluate multiple primary tumors from the same patient, but is an additional study we have planned. Subject IDM-PathT-PathPMRSpecimen YearTILs ScoreTILs InterpretationCPI ScoreCPI Interpretation1MelanomaLymph node NOSMetastatic200945LOW13LOW1MelanomaSubcutaneous tissue NOSMetastatic20108LOW2LOW2Bladder cancerUrinary bladder NOSPrimary201237LOW16LOW2Bladder cancerUrinary bladder NOSPrimary201310LOW11LOW2Bladder cancerSoft TissueMetastatic201414LOW23LOW3MelanomaBrain NOSMetastatic201058MODERATE37LOW3MelanomaDuodenum NOSMetastatic201251MODERATE41LOW4MelanomaSoft Tissue NOSMetastatic200598HIGH88HIGH4MelanomaSoft Tissue NOSMetastatic200522LOW3LOW5MelanomaMesentery NOSMetastatic201245LOW35LOW5MelanomaPeritoneum NOSMetastatic201487HIGH86HIGH6Bladder cancerUrinary bladder NOSPrimary20095LOW4LOW6Bladder cancerLung NOSMetastatic201243LOW41LOW7MelanomaSkin of Trunk NOSMetastatic20114LOW4LOW7MelanomaChest wall NOSMetastatic20122LOW1LOW7MelanomaSoft TissueMetastatic201225LOW25LOW8Lung adenocarcinomaLung right upper lobe of, NOSPrimary200999HIGH88HIGH8Lung adenocarcinomaLung right upper lobe of, NOSPrimary201688HIGH80HIGH9MelanomaLymph node NOSMetastatic20092LOW5LOW9MelanomaSmall intestine NOSMetastatic20110LOW1LOW10MelanomaSkin of Lower Extremity NOSMetastatic201216LOW8LOW10MelanomaLymph node NOSMetastatic201243LOW31LOW10MelanomaSkin of Lower Leg NOSMetastatic20134LOW13LOW11MelanomaLung left lower lobe of, NOSMetastatic201214LOW5LOW11MelanomaSkin of Scalp NOSPrimary201022LOW20LOW12Lung adenocarcinomaLung NOSPrimary201089HIGH77HIGH12Lung adenocarcinomaBrain NOSMetastatic201441LOW13LOW13MelanomaLiver NOSMetastatic201166MODERATE51MODERATE13MelanomaLymph node NOSMetastatic201147LOW13LOW14Renal cell carcinomaLung right lower lobe of, NOSMetastatic201395HIGH87HIGH14Renal cell carcinomaAdrenal gland NOSMetastatic201465MODERATE71MODERATE15Lung adenocarcinomaLung right middle lobe of, NOSPrimary201488HIGH75HIGH15Lung adenocarcinomaBrain NOSMetastatic201526LOW1LOW16MelanomaTonsil NOSMetastatic201462MODERATE53MODERATE16MelanomaSoft TissueMetastatic201513LOW1LOW17MelanomaDura Mater NOSMetastatic201553MODERATE16LOW17MelanomaLymph node NOSMetastatic201599HIGH88HIGH Citation Format: Carl D. Morrison, Jeffrey Conroy, Sean Glenn, Blake Burgher, Sarabjot Pabla, Maochun Qin, Antonios Papanicolau-Sengos, Jon Andreas, Vincent Giamo, Mary Nesline, Shipra Gandhi, Manu Pandey, Nischala Ammannagari, Kunle Odunsi, Marc Ernstoff, Mark Gardner. Tumor microenvironment heterogeneity is not identified across multiple histologically similar tumors from the same patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 620. doi:10.1158/1538-7445.AM2017-620
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-620
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 1320: Immunogenomic analysis identifies the complement pathway as a therapeutic target in STK11 mutant non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1320-1320
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1320-1320
    Abstract: Background: The use of immune PD-1/-L1 checkpoint inhibitors (ICI) has dramatically altered the treatment of advanced non-small cell lung cancer (NSCLC). However, a large proportion of patients with NSCLC do not derive clinical benefit from ICI treatment. Recent studies have identified certain genomic subsets of NSCLC as drivers of primary resistance to ICI treatment. Methods: We evaluated NSCLC patients treated at Roswell Park Comprehensive Cancer Center from 2017-2020 with successful genomic and immune profiling using a CLIA-certified laboratory developed test that included targeted next-generation genomic sequencing, PD-L1 assessment by immunohistochemistry (IHC), and targeted RNA-seq of 394 immune transcripts. Results: A total of 379 treatment-naive non-squamous NSCLC subjects were identified with 113 subjects treated with an FDA approved ICI regimen and evaluable for response. Using a gene expression signature based on differential gene expression analysis in the 113 subjects with and without disease control with ICI treatment, we performed unsupervised clustering of the larger 379 subject cohort and identified a responder (R) cluster and non-responder (NR) cluster. The R cluster was associated with high PD-L1 expression, T-cell infiltration, and KRAS mutations. The NR cluster was associated with negative PD-L1 expression, lack of T-cell infiltration, and mutations in STK11, APC/CTNNB1, and NFE2L2. Of the mutation subsets, STK11 was most associated with NR with a trend towards lower PD-L1 expression by clinical IHC, but much more significantly associated by gene expression signatures with low PD-L1 and T-cell inflammation. In our gene panel, we identified elevated TRIM29 expression in STK11 mutant NSCLC tumors and confirmed TRIM29 expression by IHC on a separate 64 subject cohort with known STK11 mutation status and archival formalin fixed paraffin embedded (FFPE) tissue. A subset of STK11 mutant NSCLC cell lines also demonstrated elevated TRIM29 expression and we generated knockouts of TRIM29 with CRISPR-Cas9 in these cell lines which resulted in decreased tumor growth in xenograft models. Using Nanostring nCounter multiplex inflammation gene expression panel on both the 64 patient FFPE cohort and TRIM29 knockout cell lines, we identified the innate immune complement pathway as a target of therapeutic interest and specifically the high expression of complement component C3 by TRIM29 high tumor cells. We then generated a syngeneic mouse model where loss of Stk11 resulted in elevated expression of Trim29 and C3 for preclinical studies to evaluate the therapeutic modulation of the complement pathway on response to ICI. Conclusion: Using a large clinical cohort of non-squamous NSCLC patients we characterized the immune environment of mutational subsets of NSCLC and identified the complement pathway as a potential therapeutic target in STK11 mutant NSCLC. Citation Format: Edwin H. Yau, Bojidar Kandar, Lei Deng, Te-An Chen, Wiam Bshara, Sean Glenn, Sarabjot Pabla, Antonios Papanicolau-Sengos, Mary Nesline, Hongbin Chen, Amy Early, Carl Morrison, Grace Dy. Immunogenomic analysis identifies the complement pathway as a therapeutic target in STK11 mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1320.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1320
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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