The Mesenchymal State Predicts Poor Disease-Free Survival in Resectable Non-Small Cell Lung Cancer

Mehta, Kunal; Moravcikova, Erika; McFall, David; Luketich, James D.; Pennathur, Arjun; Donnenberg, Albert D.; Donnenberg, Vera S.

doi:10.1016/j.athoracsur.2017.01.091

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…The presence of a robust immune infiltrate accompanying virtually all malignant pleural effusions poses a conundrum: why, in the presence abundant T cells and macrophages, does the tumor thrive and attain an aggressive and therapy resistant state ( 19 , 20 )? Although MPE are uniformly fatal, high numbers of T cells, and low numbers of neutrophils have been associated with marginally longer survival times ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells

et al. 2023

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IntroductionTreatment options for patients with malignant pleural effusions (MPE) are limited due, at least in part, to the unique environment of the pleural space, which drives an aggressive tumor state and governs the behavior of infiltrating immune cells. Modulation of the pleural environment may be a necessary step toward the development of effective treatments. We examine immune checkpoint molecule (ICM) expression on pleural T cells, the secretomes of pleural fluid, pleural infiltrating T cells (PIT), and ability to activate PIT ex vivo.MethodsICM expression was determined on freshly drained and in vitro activated PIT from breast, lung and renal cell cancer. Secretomics (63 analytes) of activated PIT, primary tumor cultures and MPE fluid was determined using Luminex technology. Complementary digital spatial proteomic profiling (42 analytes) of CD45+ MPE cells was done using the Nanostring GeoMx platform. Cytolytic activity was measured against autologous tumor targets.ResultsICM expression was low on freshy isolated PIT; regulatory T cells (T-reg) were not detectable by GeoMx. In vitro activated PIT coexpressed PD-1, LAG-3 and TIGIT but were highly cytotoxic against autologous tumor and uniquely secreted cytokines and chemokines in the > 100 pM range. These included CCL4, CCL3, granzyme B, IL-13, TNFα, IL-2 IFNγ, GM-CSF, and perforin. Activated PIT also secreted high levels of IL-6, IL-8 and sIL-6Rα, which contribute to polarization of the pleural environment toward wound healing and the epithelial to mesenchymal transition. Addition of IL-6Rα antagonist to cultures reversed tumor EMT but did not alter PIT activation, cytokine secretion or cytotoxicity.DiscussionDespite the negative environment, immune effector cells are plentiful, persist in MPE in a quiescent state, and are easily activated and expanded in culture. Low expression of ICM on native PIT may explain reported lack of responsiveness to immune checkpoint blockade. The potent cytotoxic activity of activated PIT and a proof-of-concept clinical scale GMP-expansion experiment support their promise as a cellular therapeutic. We expect that a successful approach will require combining cellular therapy with pleural conditioning using immune checkpoint blockers together with inhibitors of upstream master cytokines such as the IL-6/IL-6R axis.

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Section: Discussionmentioning

confidence: 99%

A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells

et al. 2023

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“…However, research on THY1 in LUAD is limited. High expressions of THY1 and CD44 influence the relapse-free survival in LUAD patients ( 70 ). In our analysis, THY1 was highly expressed in the wound-healing subtype and TGF-β-dominant subtype in LUAD patient ( Figure 6A ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis

Liu

Lei

et al. 2022

Front. Oncol.

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Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.

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“…Detection of the invasion markers in a carcinoma in situ lesion, or metastasis markers in a primary invasive cancer (33), or a mesenchymal transition of the overall cell surface proteome may provide early warnings of nascent aggressive disease (15). Detection of the invasion markers in a carcinoma in situ lesion, or metastasis markers in a primary invasive cancer (33), or a mesenchymal transition of the overall cell surface proteome may provide early warnings of nascent aggressive disease (15).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to markers specific to MBrCa samples, cell surface proteins marking the transition from normal to neoplastic and from neoplastic to invasive, may likewise provide important leads for prognostic markers and therapeutic targets. Detection of the invasion markers in a carcinoma in situ lesion, or metastasis markers in a primary invasive cancer (33), or a mesenchymal transition of the overall cell surface proteome may provide early warnings of nascent aggressive disease (15). Such diagnostic and prognostic markers may help distinguish aggressive from indolent tumors at the time of diagnosis, helping to guide therapeutic decisions, as well as providing mechanistic clues concerning the processes of invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Antibody‐based cell‐surface proteome profiling of metastatic breast cancer primary explants and cell lines

et al. 2018

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Flow cytometric cell surface proteomics provides a new and powerful tool to determine changes accompanying neoplastic transformation and invasion, providing clues to essential interactions with the microenvironment as well as leads for potential therapeutic targets. One of the most important advantages of flow cytometric cell surface proteomics is that it can be performed on living cells that can be sorted for further characterization and functional studies. Here, we document the surface proteome of clonogenic metastatic breast cancer (MBrCa) explants, which was strikingly similar to that of normal mesenchymal stromal cells (P = 0.017, associated with Pearson correlation coefficient) and transformed mammary epithelial cells (P = 0.022). Markers specifically upregulated on MBrCa included CD200 (Ox2), CD51/CD61 (Integrin α5/β3), CD26 (dipeptidyl peptidase-4), CD165 (c-Cbl), and CD54 (ICAM-1). Proteins progressively upregulated in a model of neoplastic transformation and invasion included CD26, CD63 (LAMP3), CD105 (Endoglin), CD107a (LAMP1), CD108 (Semaphorin 7A), CD109 (Integrin β4), CD151 (Raph blood group), and disialoganglioside G2. The proteome of the commonly used cell lines MDA-MB-231, MCF7, and BT-474 were uncorrelated with that of MBrCa (P = 1.0, 1.0, 0.9, respectively). The comparison has demonstrated the mesenchymal nature of clonogenic cells isolated by short-term culture of metastatic breast cancer, provided several leads for biomarkers and potential targets for anti-invasive therapy, including CD200, and highlighted the limitations of breast cancer cell lines for representing the cell surface biology of breast cancer. © 2017 International Society for Advancement of Cytometry.

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The Mesenchymal State Predicts Poor Disease-Free Survival in Resectable Non-Small Cell Lung Cancer

Cited by 8 publications

References 36 publications

A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells

A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells

Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis

Antibody‐based cell‐surface proteome profiling of metastatic breast cancer primary explants and cell lines

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