scholarly journals Immune System Alterations in Lung Cancer Patients

2003 ◽  
Vol 16 (2) ◽  
pp. 167-174 ◽  
Author(s):  
G. Mazzoccoli ◽  
M. Grilli ◽  
S. Carughi ◽  
F. Puzzolante ◽  
A. De Cata ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Circadian Rhythm ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Serum Levels ◽  
Neoplastic Disease ◽  
Circadian Variations

The immune system plays an important role in the defense against neoplastic disease and immune responses show temporal changes related to circadian variations of antibodies, total lymphocytes in the peripheral blood and cell mediated immune responses. In this study we evaluate, lymphocyte subpopulations and interleukin-2 (IL-2) serum levels in peripheral blood samples collected at four-hour intervals for 24-hours starting at 06.00h from ten healthy subjects aged 65–79 years (mean age ± S.E. 67.28 ±3.11) and from ten subjects suffering from untreated non small cell lung cancer aged 65–78 years (mean age ± S.E. 68.57 ± 1.81). Areas under the curve, mean diurnal levels (mean of 06.00–10.00–14.00 h) and mean nocturnal levels (mean of 18.00–22.00–02.00 h) were calculated, and the presence of circadian rhythmicity was evaluate. When we compared AUC values there was a decrease in CD8bright (T suppressor subset) and an increase in CD16 (natural killer cells) and of IL-2 serum levels in cancer patients. When we compared mean diurnal levels, CD8 (T suppressor/cytotoxic subset) and CD8bright levels were lower, and CD16 levels were higher in cancer patients. When we compared mean nocturnal levels, CD16 and CD25 (T and B activated lymphocytes with expression of the a chain of IL-2 receptor) levels were higher, while CD8, CD8bright, CD20 (total B-cells), TcRd1 (epitope of the constant domain of d chain of T-cell receptor 1) and dTcS1 (epitope of the variable domain of d chain of T-cell receptor1) levels were lower in cancer patients. A clear circadian rhythm was validated for the time-qualified changes in CD4, CD20, HLA-DR with acrophase at night, and CD8, CD8bright, CD8dim, CD16, TcRd1 and dTcS1 with acrophase in the morning in the control group. A clear circadian rhythm was validated for the time-qualified changes in CD4 with acrophase at night, in the group of cancer patients. Results obtained in our study show that lung cancer is associated with anomalies of proportion and circadian variations of lymphocyte subsets that must be considered when adoptive immunotherapy has to be planned.

Analysis of Spontaneous Vs. Vaccine-Induced Antibody Responses Against Cancer-Testis Antigen MAGE-A3 in Cancer Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5087-5087
Author(s):  
Yanran Cao ◽  
Sacha Gnjatic ◽  
Vincent G. Brichard ◽  
Tim Luetkens ◽  
Sebastian Kobold ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Specific Antibodies ◽  
Fine Specificity ◽  
Specific Memory ◽  
Cancer Testis

Abstract Abstract 5087 Background: Cancer-testis antigens (CTA) are attractive targets for cancer immunotherapy based on their tumor-restricted expression and immunogenicity. A number of CTA, including Melanoma-associated antigen 3 (MAGE-A3), are already under clinical investigation and CTA have been shown to induce strong T cell and humoral immunity in cancer patients receiving active immunotherapy. However, little is known about the fine specificity and the function of vaccine-induced humoral immune responses and it is unclear how they relate to spontaneous CTA-specific immune responses occurring in a minority of patients. Methods: We have performed a longitudinal analysis of spontaneously occurring antibody responses against the CT antigen MAGE-A3 in sera (N=1537), which were collected from patients with multiple myeloma (N=355) over a period of 6 years. Antibody titers were determined by ELISA technique and a B cell ELISPOT assay was applied to estimate the number of MAGEA3-specific memory B cells in peripheral blood of the patients. Fine specificity of the antibody responses was examined using overlapping 20mer peptides spanning the whole sequence of MAGE-A3. The given IgG subtype was determined, and the quality of MAGE-A3-specific antibodies was analyzed using western blot as well as affinity assays. Results were compared to those obtained with MAGE-A3-specific antibody responses induced by vaccination with full-length MAGE-A3 protein and adjuvants AS02B or AS15 in patients with non-small cell lung cancer (NSCLC; N=15). Results: Out of 355 myeloma patients 4 (1.1%) evidenced spontaneous antibody responses against MAGE-A3 at least at one point during the course of their disease. Spontaneously occurring anti-MAGE-A3 humoral responses were usually of low titer. In contrast, all of the vaccinated patients showed high-titered and persisting antibody responses which usually appeared around week 6 after the first application of the vaccine. Accordingly, we found high frequencies of vaccine-induced MAGE-A3-specific memory B cells in the peripheral blood of NSCLC patients while they remained undetectable in most myeloma patients. Vaccine-induced antibody responses underwent affinity maturation reaching affinity levels of spontaneous immune responses after repeated cycles of treatment. MAGE-A3-specific antibodies consisted of IgG1 and IgG3>IgG2>IgG4 subtypes in vaccinated patients whereas spontaneously occurring antibodies were mainly of the IgG2 subtype. Spontaneous as well as vaccine-induced IgG antibodies both recognized the natural full-length protein. Analysis of the fine specificity of the antibody responses revealed that vaccine-induced antibodies recognized a much larger number of MAGE-A3 epitopes than spontaneously occurring antibodies. However, both, spontaneous as well as vaccine-induced responses, most frequently and strongly recognized a specific region within the MAGE-A3 protein corresponding to amino acids 51–70. Conclusions This study demonstrates for the first time important qualitative differences between spontaneously occurring and vaccine-induced antibody responses against the MAGE-A3 antigen in cancer patients. While the potential of both types of antibody responses to promote antigen uptake and induction of T cell responses by antigen-presenting cells might differ, they both recognized the same restricted region within the MAGE-A3 protein. The latter finding might be of importance for the design of future immunotherapies targeting MAGE-A3. Disclosures: No relevant conflicts of interest to declare.

TCR repertoire analysis from peripheral blood for prognostic assessment of patients during treatment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14040-e14040
Author(s):  
Sadanand Vodala ◽  
Andrew Nguyen ◽  
Noe Rodriguez ◽  
Peter Sieling ◽  
Charles Joseph Vaske ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Poor Response ◽  
Time Points ◽  
Tcr Repertoire ◽  
Related Response

e14040 Background: Immune checkpoint inhibitors offer substantial clinical advantage to a subset of patients but predictive/novel prognostic indicators are still scarce. T cell receptors (TCRs) play a crucial role in adaptive immunity and anti-tumor immune responses. Net diversity of TCR repertoires are altered in patients receiving immune checkpoint inhibitors. To study the prognostic significance of T cell repertoires as a biomarker of immune responses in cancer patients, we characterized TCR repertoires from peripheral blood using high throughput sequencing. Methods: Total RNA from peripheral blood mononuclear cells (PBMCs) was extracted and used to generate sequencing libraries from five pancreatic cancer patients, four triple negative breast cancer (TNBC) patients and two squamous cell carcinoma (SCC+) patients. Blood draws were collected pre- and post-treatment and target lesion analysis was performed using immune-related response criteria (irRC) and Recist1.1. TCR alpha and beta CDR3s were clonotyped for each sample, and profiles of clonotype proportions were tracked through time/serial biopsies. Additionally the Shannon-Wiener diversity metric was calculated for each time point. Results: Patient samples showing consistent positive responses as measured by irRC and Recist1.1 showed TCR clones persisting throughout all time points. A TNBC super responder showed dramatic increases in mean Shannon-Wiener index from 74 prior treatment to 1177 at first biopsy post treatment (34% decrease by irRC and 26% by Recist1.1 analysis) and achieved an index as high as 3516 in a subsequent biopsy (83% and 64% decrease by irRC and Recist 1.1 respectively). Patients that showed poor response by irRC and Recist1.1 showed TCR clones that were in constant flux. Loss of clonality and/or decrease in absolute numbers was observed in previous and later time points. Conclusions: Patients that show positive response had TCR clones that were stable, which may indicate an existing immune related response towards their tumor. Therapy would allow these existing T-cells to overcome blockade by tumor cells. Patients showing poor response show a TCR repertoire that is constantly changing potentially indicating that the tumor cells are not eliciting a strong T cell specific response. Further functional studies of T cell populations would expand our understanding of T cell based immune therapies.

Characteristics of T-cell receptor repertoire between lung cancer patients and healthy people.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20728-e20728 ◽  
Author(s):  
Naixin Liang ◽  
Si Chen ◽  
Yuting Yi ◽  
Yan-Fang Guan ◽  
Xuefeng Xia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Shannon Index ◽  
Shannon’S Entropy ◽  
Lung Cancer Patients ◽  
Shannon's Entropy ◽  
Tcr Repertoire

e20728 Background: Deep sequencing studies on T cell receptor (TCR) repertoire have provided a wealth of information, such as immune status, virus infection history and so on. As we all known, the thymus begins to involute at the time of birth, so does the immune system. We can use TCR sequence to describe changes in human’s immune system with age, the difference between males and females and immune stat of cancers. Methods: We analyzed TCRβrepertoire in 334 healthy individuals without cancer, aged 2–83 years, and 207 lung cancers. In detail, genomic DNA was extracted from peripheral blood and used to amplified and sequenced the CDR3 region of rearranged TCRβ genes. Finally, we got the relative frequencies of individual T cell clones. Shannon’s entropy was calculated on the clonal abundance of all productive TCR sequences. The normalized Shannon’s entropy (Shannon index) was determined by dividing Shannon’s entropy by the natural logarithm of the number of unique productive TCR sequences. HEC was defined by a CDR3 aa clonotype clonal frequency exceeding 0.1%. Results: Analysis had been made to test the age relationship among a cluster of commonly used immune parameters, such as Shannon’s entropy, clonality and so on. Two outcomes, Shannon index and HEC, had showed a more closed correlation with age. Shannon indexs were significantly decreasing with age (p = 6.2×10-11), while HECs increased with age (p = 5.3×10-10) . Comparison of the peripheral blood T cell repertoire diversity between male and female, we found TCRβdiversity decreases more rapidly in 20 to 40 years for males than for females. No gender difference was observed in the youngest cohort and the oldest age cohort. Lung cancer patients has a lower T cell diversity compared with health people aged 40 years or more (6.43±1.30 vs 6.71±1.70, p = 6.3×10-5). Conclusions: Our data suggest that the human peripheral blood TCR repertoire diversity decrease from young ( < 20 years) to middle-aged ( 20 to 65 years ) to elderly adults ( > 65 years). Moreover, TCR repertoire displays significant gender difference in the 20-40 years age group. Lung cancer patients suffer a poorer immune state than healthy people.

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.

T-Cell Immunity to the Folate Receptor Alpha Is Prevalent in Women With Breast or Ovarian Cancer

2006 ◽  
Vol 24 (26) ◽  
pp. 4254-4261 ◽  
Author(s):  
Keith L. Knutson ◽  
Christopher J. Krco ◽  
Courtney L. Erskine ◽  
Karin Goodman ◽  
Linda E. Kelemen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune System ◽  
T Cell ◽  
Cancer Patients ◽  
Folate Receptor ◽  
Prediction Algorithm ◽  
Amino Terminus ◽  
Folate Receptor Alpha ◽  
Receptor Alpha ◽  
Healthy Donors

Purpose Studies have demonstrated that the generation of immunity to tumor antigens is associated with improved prognosis for many cancers. A candidate antigen is the folate receptor alpha (FRα), which is overexpressed in breast and ovarian cancers. Our goal in this study was to attain a better understanding of the extent of endogenous FRα immunity. Methods Using a CD4+ T cell epitope prediction algorithm, we predicted promiscuous epitopes of FRα, and tested for immunity in 30 breast (n = 17) or ovarian (n = 13) cancer patients and 18 healthy donors using enzyme-linked immunospot analysis. Results Fourteen peptides were predicted, seven each from the carboxy- and amino-terminus halves of the protein. More than 70% of patients demonstrated immunity to at least one FRα peptide. Patients responded to an average of 3 ± 0.5 peptides, whereas healthy donors responded to 1 ± 0.4 peptides (P = .004). Five peptides were recognized by more than 25% of patients. Responses to three peptides were higher (P < .05) in patients than in healthy donors, suggesting augmented immunity. Compared with healthy individuals, patients developed higher immunity to the amino-terminus half of the receptor (P = .03). There was no difference between each group in the responses to nonspecific (P = .2) and viral stimuli (P = .5). Lastly, patients demonstrated elevated levels of FRα antibodies consistent with a coordinated immune response. Conclusion These findings demonstrate that the FRα is a target of the immune system in breast and ovarian cancer patients. Understanding which antigens are targeted by the immune system may be important for prognosis or immune-based therapies.

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