183 Overcoming immunotherapy resistance in T cell-inflamed lung cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A197-A197
Author(s):  
Brendan Horton ◽  
Brendan Horton ◽  
Duncan Morgan ◽  
Noor Momin ◽  
Vidit Bhandarkar ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cancer Patients ◽  
Rna Sequencing ◽  
Mechanistic Study ◽  
Nsclc Cell Line ◽  
Effector Molecule ◽  
Effector Molecules

BackgroundTumor infiltrating T cells (TIL) are highly correlated with response to checkpoint blockade immunotherapy (CBT) in melanoma. However, in non-small cell lung cancer (NSCLC), 61% of patients have TIL, but only 32% respond to CBT. It is unknown how these T cell-inflamed tumors are resistant to CBT. Understanding and overcoming this resistance would greatly increase the number of cancer patients who benefit from CBT.MethodsTo understand lung-specific anti-tumor immune responses, a NSCLC cell line derived from an autochthonous murine lung cancer (KP cell line) was transplanted into syngeneic C57BL/6 mice subcutaneously or intravenously. To study antigen-specific responses, the KP cell line was engineered with SIY and 2C TCR transgenic T cells, which are specific for SIY, were adoptively transferred into tumor-bearing animals.ResultsSubcutaneous KP tumors responded to CBT (aCTLA-4 and aPD-L1) with significant tumor regression while lung KP tumors were CBT resistant. Immunohistochemistry found that this was not due to lack of T cell infiltration, as lung tumors contained 10-fold higher numbers of CD8+ TIL than subcutaneous tumors. Single cell RNA sequencing of TIL uncovered that CD8+ TIL in lung lesions had blunted effector molecule expression that correlated with a lack of IL-2 signaling. Adoptive transfer of naïve, tumor-reactive 2C T cells resulted in equally robust T cell proliferation in both the inguinal and mediastinal lymph nodes (LNs). However, RNA sequencing of adoptively transferred 2C T cells isolated 3-days after transfer from draining LNs identified that T cells activated in the mediastinal LN had reduced levels of IL-2 signaling and blunted effector functions early during priming. Flow cytometry confirmed that T cells primed in the mediastinal LNs did not express CD25, GZMB, or IFN-g, while T cells in inguinal LNs upregulated all three of these effector molecules. Delivery of IL-2 and IL-12 during priming was sufficient to restore effector molecule expression on 2C T cells in mediastinal LNs. Analysis of published patient data identified that a subset of lung cancer patients showed a sizable population of CD8+ TIL with low IL-2 signaling and low expression of effector molecules, including common targets of CBT.ConclusionsImmunotherapy resistance in T cell-inflamed tumors is due to defective CD8+ T cell effector differentiation. IL-2-based therapies could enhance differentiation of functional CD8+ effector T cells and could turn immunotherapy resistant tumors to immunotherapy sensitive tumors. This is the first mechanistic study providing evidence for a distinct type of T cell dysfunction resistant to current CBT.Ethics ApprovalThis study was approved by MIT’s Committee on Animal Care, protocol number 0220-006-23.

scholarly journals Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation

2002 ◽  
Vol 168 (9) ◽  
pp. 4272-4276 ◽  
Author(s):  
Edward Y. Woo ◽  
Heidi Yeh ◽  
Christina S. Chu ◽  
Katia Schlienger ◽  
Richard G. Carroll ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Cutting Edge ◽  
T Cell Proliferation ◽  
Lung Cancer Patients

scholarly journals Activin-A Impedes the Establishment of CD4+ T Cell Exhaustion and Enhances Anti-Tumor Immunity in the Lung

2021 ◽  
Author(s):  
Ioannis Morianos ◽  
Aikaterini Tsitsopoulou ◽  
Konstantinos Potaris ◽  
Dimitrios Valakos ◽  
Ourania Fari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Tumor Immunity ◽  
Lung Tumor ◽  
Activin A ◽  
Type I ◽  
Lung Cancer Patients ◽  
Tumor Bearing

Abstract Background: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer.Methods: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients.Results: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells.Conclusions: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

scholarly journals Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Ioannis Morianos ◽  
Aikaterini Tsitsopoulou ◽  
Konstantinos Potaris ◽  
Dimitrios Valakos ◽  
Ourania Fari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Tumor Immunity ◽  
Lung Tumor ◽  
Activin A ◽  
Type I ◽  
Lung Cancer Patients ◽  
Tumor Bearing

Abstract Background Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. Methods To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4−/−-tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Results Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4−/− recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. Conclusions In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

scholarly journals Characterising Tumour and Microenvironmental Responses to R-CHOP in Immunocompetent Mouse Models of DLBCL

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2401-2401
Author(s):  
Bernard D Maybury ◽  
Findlay Bewicke-Copley ◽  
Peter Johnson ◽  
Jude Fitzgibbon ◽  
Dinis Pedro Calado
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Line ◽  
Rna Sequencing ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Lymphoma Cells ◽  
Pre Treatment

Abstract R-CHOP chemoimmunotherapy has been the standard of care for diffuse large B cell lymphoma (DLBCL) for 20 years. The lymphoma and microenvironment responses to R-CHOP have not been studied in detail in an experimental setting. Here we describe the early effects of R-CHOP on lymphoma cells and infiltrating T cells in novel mouse models of DLBCL. Using cre-lox recombination to induce B cell-specific overexpression of MYC, IKK2 and BLIMP1 drives the formation of unique high grade B cell lymphomas with an activated B cell (ABC) phenotype and an intact immune environment. Using flow cytometry and RNA sequencing we compare the response to R-CHOP in these mice with the response in a cell line lymphoma model. We also performed partial splenectomy prior to R-CHOP treatment to study paired samples pre-treatment and at relapse by whole-exome and RNA sequencing. Treatment with anti-CD20 alone induced very few changes in lymphoma cells in either model, but CHOP chemotherapy in combination with rituximab induced changes in lymphoma cell and T cell phenotypes. In particular, extracellular matrix and cell adhesion gene signatures were enriched in lymphoma cells after treatment, in both disease models studied. After injection of the cell line, memory populations of CD8+ T cells are expanded but this change is reversed by chemotherapy, whereas in the cre-lox conditional model 40% of CD8+ T cells are exhausted with smaller chemotherapy-associated changes. In the paired pre-treatment/relapse samples we observed clonal selection and increased mutation burden at relapse, associated with diverse transcriptional changes. Mutations were newly detected or expanded at relapse in various lymphoma-associated genes including Trp53, Samhd1 and Ubr5. Our results suggest that DLBCL responses to treatment and biology at relapse are principally driven by tumour-specific factors, but there are some commonalities across model systems which may be amenable to therapeutic modulation. The differences in T cell responses between conditional tumours and cell-line tumours demonstrate the limitations of cell lines for studying treatment responses in vivo. Figure 1 Figure 1. Disclosures Johnson: Boehringer Ingelheim: Consultancy; Janssen: Consultancy; Kite Pharma: Honoraria; Oncimmune: Consultancy; Epizyme: Consultancy, Research Funding; Bristol-Myers: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Celgene: Honoraria; Kymera: Honoraria. Fitzgibbon: Epizyme: Research Funding. Calado: Myricx Pharma: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Patents & Royalties: Cancer Treatments. WO patent WO 2020/128475 A1 (2020).

scholarly journals Highly differentiated CD4 T cells Unequivocally Identify Primary Resistance and Risk of Hyperprogression to PD-L1/PD-1 Immune Checkpoint Blockade in Lung Cancer

2018 ◽  
Author(s):  
Miren Zuazo-Ibarra ◽  
Hugo Arasanz ◽  
Gonzalo Fernández-Hinojal ◽  
Gato-Cañas María ◽  
Berta Hernández-Marín ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Cd4 T Cells ◽  
Critical Issue ◽  
Immune Checkpoint Blockade ◽  
Cd4 T Cell ◽  
Primary Resistance ◽  
Lung Cancer Patients

AbstractThe majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This therapy may even accelerate progression and death in a group of patients called hyperprogressors. Here we demonstrate that the efficacy of PD-L1/PD-1 blockade therapy relies on baseline circulating highly-differentiated CD28− CD27− CD4 T cells (THD cells), which segregate patients in two non-overlapping groups. THD cells in cancer patients mostly comprised of central memory subsets that potently co-upregulated PD-1 and LAG3 upon antigen recognition. Low baseline THD numbers unequivocally identified intrinsic non-responders and hyperprogressors, whom aberrantly responded to therapy with a potent systemic proliferative THD cell burst. Responder patients showed significant reductions in systemic CD4 THD cells throughout therapy linked to expansion of the CD28+ CD27+ CD4 T cell compartment. Quantification of THD cells from peripheral blood samples prior to therapy allows identification of non-responders, hyperprogressors and responders, a critical issue in clinical oncology. These results place CD4 T cell responses at the center of anti-tumor immunity.

scholarly journals Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 155
Author(s):  
Pankaj Ahluwalia ◽  
Meenakshi Ahluwalia ◽  
Ashis K. Mondal ◽  
Nikhil Sahajpal ◽  
Vamsi Kota ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
High Risk ◽  
Lung Adenocarcinoma ◽  
Risk Group ◽  
High Risk Group ◽  
Free Survival ◽  
Cell Death Pathways

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan–Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28–2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

scholarly journals Tin Mesoporphyrin Selectively Reduces Non-Small-Cell Lung Cancer Cell Line A549 Proliferation by Interfering with Heme Oxygenase and Glutathione Systems

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 917
Author(s):  
Valeria Sorrenti ◽  
Agata Grazia D’Amico ◽  
Ignazio Barbagallo ◽  
Valeria Consoli ◽  
Salvo Grosso ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Heme Oxygenase ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Antioxidant Systems ◽  
Nsclc Cell Line ◽  
Small Cell Lung

In order to maintain redox homeostasis, non-small-cell lung cancer (NSCLC) increases the activation of many antioxidant systems, including the heme-oxygenase (HO) system. The overexpression of HO-1 has been often associated with chemoresistance and tumor aggressiveness. Our results clearly showed an overexpression of the HO-1 protein in A549 NSCLC cell lines compared to that in non-cancerous cells. Thus, we hypothesized that “off-label” use of tin mesoporphyrin, a well-known HO activity inhibitor clinically used for neonatal hyperbilirubinemia, has potential use as an anti-cancer agent. The pharmacological inhibition of HO activity caused a reduction in cell proliferation and migration of A549. SnMP treatment caused an increase in oxidative stress, as demonstrated by the upregulation of reactive oxygen species (ROS) and the depletion of glutathione (GSH) content. To support these data, Western blot analysis was performed to analyze glucose-6-phosphate dehydrogenase (G6PD), TP53-induced glycolysis and the apoptosis regulator (TIGAR), and the glutamate cysteine ligase catalytic (GCLC) subunit, as they represent the main regulators of the pentose phosphate pathway (PPP) and glutathione synthesis, respectively. NCI-H292, a subtype of the NSCLC cell line, did not respond to SnMP treatment, possibly due to low basal levels of HO-1, suggesting a cellular-dependent antitumorigenic effect. Altogether, our results suggest HO activity inhibition may represent a potential target for selective chemotherapy in lung cancer subtypes.

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