Evasion of Cytotoxic Lymphocyte and Pulmonary Macrophage-Mediated Immune Responses in Lung Cancer

We have investigated the effects of interleukin (IL)-12 (natural killer cell stimulatory factor/cytotoxic lymphocyte maturation factor) on the proliferation of murine myeloid and lymphohematopoietic progenitors in methylcellulose culture. In the presence of erythropoietin (Ep), IL-12 alone failed to support colony formation by mononuclear and enriched marrow cells of normal mice. Steel factor (SF) alone supported primarily formation of granulocyte/macrophage (GM) colony formation. However, the combination of the two cytokines yielded a significant number of multilineage colonies. When tested on marrow cells from 5- fluorouracil (5-FU)-treated mice, the combination of IL-12 and SF, but not the single factors, was effective in support of formation of various types of colonies. Approximately 25% of these colonies yielded pre-B-cell colonies when replated in secondary culture containing SF and IL-7, indicating that IL-12 can interact with SF in supporting the development of primitive lymphohematopoietic progenitors. These results demonstrate that IL-12, a cytokine believed to be involved in the development of cell-mediated immune responses, has a wider range of activity, including committed myeloid and multipotent lymphohematopoietic progenitors.

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P3.04-27 An Allogeneic Tumor Cell Lysate Vaccine Induces Immune Responses to Lung Cancer Associated Antigens: Preliminary Results of a Phase II Study

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.08.1734 ◽

2018 ◽

Vol 13 (10) ◽

pp. S932

Author(s):

M. Zhang ◽

J. Hong ◽

T. Kunst ◽

C. Bond ◽

J. Yeray ◽

...

Keyword(s):

Lung Cancer ◽

Immune Responses ◽

Tumor Cell ◽

Phase Ii ◽

Phase Ii Study ◽

Preliminary Results ◽

Cell Lysate ◽

Allogeneic Tumor ◽

Tumor Cell Lysate ◽

Allogeneic Tumor Cell

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Abstract 2394: Spontaneous immune responses against XAGE-1b in patients with non-small cell lung cancer (NSCLC)

10.1158/1538-7445.am10-2394 ◽

2010 ◽

Author(s):

Yoshihiro Ohue ◽

Shingo Eikawa ◽

Yu Mizote ◽

Nami Okazaki ◽

Midori Isobe ◽

...

Keyword(s):

Lung Cancer ◽

Immune Responses ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung

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Abstract 5364: Correlation of immune responses and overall survival in a phase II study of belagenpumatucel-L, an allogeneic tumor cell vaccine, in non-small cell lung cancer (NSCLC)

10.1158/1538-7445.am2012-5364 ◽

2012 ◽

Author(s):

Daniel L. Shawler ◽

Alex Tong ◽

Lily Liu ◽

Ewa Carrier ◽

Charles S. Davis ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Immune Responses ◽

Tumor Cell ◽

Phase Ii Study ◽

Small Cell ◽

Cell Vaccine ◽

Small Cell Lung ◽

Tumor Cell Vaccine ◽

Allogeneic Tumor Cell

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Abstract 5375: Large, polymorphonuclear circulating cancer-associated cell with dual epithelial and macrophage/myeloid phenotype is prognostic in non-small cell lung cancer and has an impact on anti-tumor immune responses

10.1158/1538-7445.am2020-5375 ◽

2020 ◽

Author(s):

Yariswamy Manjunath ◽

Kanve N. Suvilesh ◽

Diego M. Avella ◽

Eric T. Kimchi ◽

Kevin F. Staveley-O'Carroll ◽

...

Keyword(s):

Lung Cancer ◽

Immune Responses ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung

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Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000316 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000316 ◽

Cited By ~ 1

Author(s):

Takahide Toyoda ◽

Toshiko Kamata ◽

Kazuhisa Tanaka ◽

Fumie Ihara ◽

Mariko Takami ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Adverse Events ◽

Immune Responses ◽

Survival Time ◽

Phase Ii ◽

Small Cell ◽

Small Cell Lung ◽

Inkt Cells ◽

Antigen Presenting

BackgroundInvariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC.MethodsPatients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan.ResultsThirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs.ConclusionsThe intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy.Trial registration numberUMIN000007321.

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Comparison of circadian characteristics for cytotoxic lymphocyte subsets in non-small cell lung cancer patients versus controls

Clinical and Experimental Medicine ◽

10.1007/s10238-011-0153-6 ◽

2011 ◽

Vol 12 (3) ◽

pp. 181-194 ◽

Cited By ~ 9

Author(s):

Gianluigi Mazzoccoli ◽

Robert B. Sothern ◽

Paola Parrella ◽

Lucia A. Muscarella ◽

Vito Michele Fazio ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Patients ◽

Cell Lung Cancer ◽

Lymphocyte Subsets ◽

Small Cell ◽

Small Cell Lung ◽

Cytotoxic Lymphocyte ◽

Lung Cancer Patients

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Engineering the Cancer Genome

Blood ◽

10.1182/blood.v126.23.sci-19.sci-19 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-19-SCI-19

Author(s):

Tyler Jacks

Keyword(s):

Lung Cancer ◽

Immune Responses ◽

Tumor Progression ◽

Nk Cell ◽

Conflicts Of Interest ◽

Wnt Signaling Pathway ◽

Cancer Genome ◽

Lineage Tracing ◽

Cancer Genes ◽

T Cell Antigens

Abstract Over the past several years, my laboratory has employed gene targeting technology to create a series of mouse models of cancer that share genetic and pathological features of the cognate diseases in humans. We have focused particularly on models of lung cancer, both adenocarcinoma and small cell lung cancer. These models have been subjected to various types of molecular characterization, including mRNA profiling and exome/whole-genome sequencing. These efforts have defined genes and pathways that promote tumor progression and metastasis, including in the case of the adenocarcinoma model down-regulation of the lineage-restricted transcription factor Nkx2.1 and other transcriptional regulators that are involved in inducing and enforcing various differentiation states that might limit tumor progression. We have also studied the involvement of subpopulations of tumor cells in this model in which the Wnt signaling pathway is active. Data from lineage tracing experiments are consistent with this population having increased tumor propagating potential. In order to functionally characterize these and other cancer genes, we have recently developed methods to mutate genes in developing tumors using the CRISPR/Cas9 system. Using tri-functional lentiviral, we have developed tumors that have undergone Cas9-mediated mutation of a series of genes of interest. Several examples of the application of this method will be reviewed. As another example of cancer genome manipulation, we have engineered tumors of the lung and other sites to express specific T cell antigens and/or NK cell ligands. These models have allowed a detailed investigation of adaptive and innate immune responses to a developing tumor. We have used the models to explore mechanisms of immune suppression in cancer and develop methods to elicit improved anti-tumor immune responses. Disclosures No relevant conflicts of interest to declare.

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Interleukin-15 expression in lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21064 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21064-e21064 ◽

Cited By ~ 2

Author(s):

Faisal Adhami ◽

Jason C Steel ◽

John Charles Morris

Keyword(s):

Lung Cancer ◽

Immune Responses ◽

Internal Control ◽

Cell Activation ◽

Nk Cell ◽

Stage Iv ◽

Normal Lung ◽

Down Regulation ◽

Lung Cancers ◽

Interleukin 15

e21064 Background: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that stimulates the differentiation and proliferation of T, B, and NK cells. IL-15 is normally tightly bound by its receptor, IL-15Rα. Dendritic cells and monocytes/macrophages primarily express both IL-15 and IL-15-Rα; however, expression has been detected on epithelial cells including those of the lung. In the lung, IL-15 is thought to play a role in the induction of immune responses to infection. Over expression of IL-15 has been shown to induce NK cell activation and cytotoxic T-lymphocyte (CTL) responses leading to tumor regression. Little is known about IL-15 or IL-15Rα expression in lung cancer. Methods: mRNA from 146 primary lung cancers were analyzed by multiplex qPCR for expression of IL-15, IL-15Rα and b-actin (internal control) and compared to expression in normal lung tissue from 45 patients. Of the 146 patients, 50 were stage I (IA=20, IB=30), 49 stage II (IIA=9, IIB=40), 36 stage III (IIIA=18, IIIB=18), and 11 stage IV. Results: Comparing the expression of IL-15 between normal lung and tumor, we found tumors expressed significantly less IL-15 than normal lung (P<0.001). Lung cancers at any given stage, expressed significantly less IL-15 than that seen in normal lung. When comparing stages, stage IV tumors expressed significantly less IL-15 than tumors of stages I (P=0.021), II (P=0.020), or III (P=0.024). There was no difference in expression between stages I, II or III (P>0.05). When examining the expression of IL-15Rα we found no differences between normal lung and tumor. No differences were seen between normal lung and stages I-IIIA; however, significantly less IL-15Rα expression was noted in stages IIIB and IV compared to normal lung. Between stages, stages I and II had significantly more IL-15Rα expression than stage IV tumors. There were no differences between stages I, II and III. Conclusions: Pro-inflammatory cytokines such as IL-15 may be important for the induction of lung immunity. IL-15 expression is down regulated in lung cancers and this down regulation increases with stage. We posit that the down regulation of IL-15 by lung cancers may aid in their evasion of immune responses allowing progression and dissemination of tumor.

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