The Functional Deficiency of B Lymphocytes in Patients with Lung Cancer is Due to Inadequate T-Cell Help and Excessive Suppression by T and Non-T Cells

1989 ◽  
Vol 7 (1) ◽  
pp. 7-16 ◽  
Author(s):  
M. Venkataraman ◽  
D. S. Rao ◽  
B. S. Iyer ◽  
MP. Westerman
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
B Lymphocytes ◽  
T Cell Help ◽  
Functional Deficiency

scholarly journals Role of B lymphocytes in cell-mediated immunity. I. Requirement for T cells or T-cell products for antigen-induced B-cell activation.

1976 ◽  
Vol 144 (5) ◽  
pp. 1175-1187 ◽  
Author(s):  
S M Wahl ◽  
D L Rosenstreich
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Chemotactic Factor ◽  
Cell Mediated Immunity ◽  
B Cell Activation ◽  
T Cell Factor ◽  
T Cell Help

Although B lymphocytes can be triggered by B-cell mitogens and by certain other molecules to produce lymphokines, they do not produce lymphokines when stimulated with specific soluble protein antigens. We have investigated whether T-cell help would enable B cells to produce lymphokines when activated by antigens. Addition of small numbers of T cells to B-cell cultures resulted in significant production of a monocyte chemotactic factor. T cells could be replaced by supernates of antigen-stimulated T cells, demonstrating both that the chemotactic factor was B-cell-dervied and that T-cell help was mediated by a soluble factor. Although the T-cell factor was nonantigen specific, B-cell activation required the presence of both antigen and T-cell factor. Thus, it appears that although dependent upon T cells, B lymphocytes may play an important role in amplification of cell-mediated immune responses.

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.

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 Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

scholarly journals Requirement for T cells in the production of migration inhibitory factor.

1975 ◽  
Vol 142 (5) ◽  
pp. 1306-1311 ◽  
Author(s):  
B R Bloom ◽  
E Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Lymphocytes ◽  
Cell Function ◽  
Plaque Assay ◽  
Quantitative Measure ◽  
Immune Response Gene ◽  
Migration Inhibition ◽  
Qualitative Assay ◽  
Gene Restriction

The question whether B lymphocytes are capable of being activated by antigen in the absence of functional T cells was investigated in a model that excludes participation of T cells by virtue of an immune response gene restriction. Strain 2 guinea pigs are capable of responding to immunization with DNP-PLL, whereas strain 13 animals are not. In the present experiments, animals of both strains were immunized with DNP-PLL complexed to ovalbumin (DNP-PLL-Ova) under conditions in which equal titers of antibodies to DNP were produced by both strains. The failure of T cells of strain 13 animals to respond to DNP-PLL was confirmed by the virus plaque assay. While spleen cells from both strains produced MIF after stimulation with DNP-PLL-Ova, in response to DNP-PLL only strain 2 spleens were able to produce MIF. Cells from neither strain could be activated by DNP-guinea pig albumin to produce MIF. We conclude that B lymphocytes are incapable of being stimulated by antigen in the absence of T cells, and that MIF production is a thymus-dependent response. While the results indicate that MIF production is a valid qualitative assay for T-cell competence, since MIF can be produced by B and T cells, the degree of migration inhibition cannot be regarded as a quantitative measure of T-cell function.

scholarly journals 665 Transcriptional landscape of tumor-reactive TIL in lung cancer and melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A693-A693
Author(s):  
Jiajia Zhang ◽  
Justina Caushi ◽  
Boyang Zhang ◽  
Zhicheng Ji ◽  
Taibo Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Informed Consent ◽  
T Cell ◽  
Cancer Center ◽  
Lung Cancers ◽  
Functional Assays ◽  
Link Type ◽  
Institutional Review

BackgroundMelanoma and lung cancers have two of the highest response rates to immune checkpoint inhibitors (ICIs).1 However, patients may respond unpredictably, partly due to heterogeneity in the quantity and quality of tumor-specific T cells. In this study, we performed an integrated transcriptomic analysis of anti-tumor CD8+ TIL from non-small cell lung cancer (NSCLC) and melanoma. Our goal was to study the global transcriptomic landscape of tumor-specific T cells and to compare their functional programming in lung cancer vs. melanoma.MethodsTIL from 19 patients (15 NSCLC and 3 melanoma) were sequenced using combined single-cell (sc) RNA-seq/TCR-seq. All NSCLC patients received neoadjuvant anti-PD-1 (nivolumab, NCT02259621) whereas melanoma patients received a personal neoantigen vaccine (NCT01970358). Neoantigen-, tumor-associated antigen-, and viral-specific CD8+ T cell clonotypes were identified using functional assays and were validated by TCR cloning as previously described.2 3 Transcriptional profiles of antigen-specific T cells were identified using the TCRβ CDR3 as a barcode to link with the antigen specificity output from the functional assays. The prevalence, phenotype, and differentiation trajectory of tumor-specific T cells were compared between the two cancer types.ResultsA total of 175,826 CD8+ TIL were analyzed, of which 30,174 single cells were from the melanoma cohort and 145,652 were from the NSCLC cohort. Tumor-specific T cells were detected at variable frequencies among CD8+ TIL (median=1.2%, range 0.01%–35.8%) across nine patients, with melanoma having more clonal tumor-specific T cells as compared to NSCLC. CD8+ TIL from melanoma were more enriched in an activated tissue resident T cell (TRM) cluster characterized by upregulated expression of CXCL13, CRTAM, 4-1BB, XCL1/2, and FABP5, whereas those from NSCLC have a greater representation of a cytotoxic TRM cluster with an exhaustion signature (coexpression of GZMB, GZMH, PDCD1, and CTLA4). Distinct from EBV-specific T cells and flu-specific T cells, tumor-specific T cells primarily resided in TRM clusters in both cancers. More MANA-specific TIL from melanoma presented with an effector phenotype and were more proliferative as compared to those from NSCLC. To reveal the differentiation trajectory and regulatory programs of tumor-specific T cells upon tumor recognition and association with response to ICIs, pseudotime/velocity analysis of tumor-specific TIL is underway.ConclusionsThis is the first analysis to inform on the global transcriptomic landscape of tumor-specific CD8+ TIL in lung cancer and melanoma at single cell resolution. This provides a useful framework to study the underlying mechanisms of T cell exhaustion and dysfunction in human cancer.Trial RegistrationNCT02259621,NCT01970358ReferencesYarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. The New England Journal of Medicine 2017;377(25):2500.Caushi JX, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 2021;1–7.Oliveira G, et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 2021;1–7.Ethics ApprovalThe melanoma clinical trial was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board (IRB) (NCT01970358). The NSCLC clinical trial was approved by the Institutional Review Boards (IRB) at Johns Hopkins University (JHU) and Memorial Sloan Kettering Cancer Center (NCT02259621). All participants gave informed consent before taking part.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Absence of CD4+ T cell help generates corrupt CD8+ effector T cells in sarcoma-bearing Swiss mice treated with NLGP vaccine

2016 ◽  
Vol 175 ◽  
pp. 31-39 ◽  
Author(s):  
Sarbari Ghosh ◽  
Madhurima Sarkar ◽  
Tithi Ghosh ◽  
Ipsita Guha ◽  
Avishek Bhuniya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Cd4 T Cell ◽  
Swiss Mice ◽  
Cd4 T Cell Help ◽  
T Cell Help

scholarly journals FOXA1+ regulatory T cells: A novel T cell subset that suppresses antitumor immunity in lung cancer

2019 ◽  
Vol 514 (1) ◽  
pp. 308-315 ◽  
Author(s):  
Jinyan Liang ◽  
Chen Tian ◽  
Yulan Zeng ◽  
Qifan Yang ◽  
Yangyang Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Antitumor Immunity ◽  
Cell Subset ◽  
T Cell Subset

scholarly journals Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non alpha/beta" T cells.

1996 ◽  
Vol 183 (5) ◽  
pp. 2271-2282 ◽  
Author(s):  
L Wen ◽  
W Pao ◽  
F S Wong ◽  
Q Peng ◽  
J Craft ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Cell Receptor ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Autoantibody Production ◽  
Ige Synthesis ◽  
Alpha Beta ◽  
T Cell Help

The production of class-switched antibodies, particularly immunoglobulin (Ig) G1 and IgE, occurs efficiently in T cell receptor (TCR) alpha-/- mice that are congenitally devoid of alpha/beta T cells. This finding runs counter to a wealth of data indicating that IgG1 and IgE synthesis are largely dependent on the collaboration between B and alpha/beta T cells. Furthermore, many of the antibodies synthesized in TCR alpha-/- mice are reactive to a similar spectrum of self-antigens as that targeted by autoantibodies characterizing human systemic lupus erythematosus (SLE). SLE, too, is most commonly regarded as an alpha/beta T cell-mediated condition. To distinguish whether the development of autoantibodies in TCR alpha-/- mice is due to an intrinsic de-regulation of B cells, or to a heretofore poorly characterized collaboration between B and "non-alpha/beta T" cells, the phenotype has been reconstituted by transfer of various populations of B and non-alpha/beta T cells including cloned gamma/delta T cells derived from TCR alpha-/- mice, to severe combined immunodeficient (SCID) mice. The results establish that the reproducible production of IgG1 (including autoantibodies) is a product of non-alpha/beta T cell help that can be provided by gamma/delta T cells. This type of B-T collaboration sustains the production of germinal centers, lymphoid follicles that ordinarily are anatomical signatures of alpha/beta T-B cell collaboration. Thus, non-alpha/beta T cell help may drive Ig synthesis and autoreactivity under various circumstances, especially in cases of alpha/beta T cell immunodeficiency.

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