| 1. |
|
|
| 2. |
|
|
| 3. |
- Diaconu, Nicolae-Costin, et al.
(author)
-
Increase in CD30 ligand/CD153 and TNF-alpha expressing mast cells in basal cell carcinoma
- 2007
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 56:9, s. 1407-1415
-
Journal article (other academic/artistic)abstract
- Mast cells are a significant source of tumor necrosis factor (TNF) superfamily members, such as TNF-alpha, CD30 ligand/CD153 (CD30L) and CD40L/CD154. Furthermore, the expression of some of these proteins in mast cells has been associated with tumorigenesis, and mast cells have been found to be increased in number in thebasal cell carcinoma (BCC) lesion. In this study, we have examined the expression ofTNF-alpha, CD30L and CD40L immunoreactivity in mast cells in the healthy-looking skin and lesional skin of ten patients with superficial spreading BCC. Also, the counterparts of these molecules, TNF receptor (TNFR) I and II as well as CD30 and CD40, were analysed immunohistochemically. We found that numbers of mast cells and Kit-positive cells were significantly increased in the dermal BCC lesion. The percentage of CD30L-positive mastcells and the number of CD30-positive cells were significantly increased in the upper dermis of the BCC lesion as well. In addition, the numbers of TNF-alpha-positive mast cellsand cells with TNFRI and TNFRII were markedly increased in the upper lesional dermis. Incontrast, no mast cells positive for CD40L could be detected, even though the lesional dermis contained increased numbers of CD40 positive cells. The BCC epithelium was positive for TNFRI, TNFRII and CD40, but not for CD30, though the larger basal buds appeared to be less intensely stained for TNFRI and CD40. In conclusion, mast cellspositive for CD30L and TNF-alpha, but not CD40L, are increased in number in the lesional dermis in BCC. These data suggest plausible pathways whereby mast cells can be activated and to interact with other cells and thereby contribute to the tumorigenesis inBCC.
|
|
| 4. |
|
|
| 5. |
- Hanson, Mikael G. V., et al.
(author)
-
A short-term dietary supplementation with high doses of vitamin E increases NK cell cytolytic activity in advanced colorectal cancer patients
- 2007
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 56:7, s. 973-984
-
Journal article (peer-reviewed)abstract
- Cancer patients with advanced disease display signs of immune suppression, which constitute a major obstacle for effective immunotherapy. Both T cells and NK cells are affected by a multitude of mechanisms of which the generation of reactive oxygen species is of major importance. Therefore, we hypothesized that two weeks of high-dose treatment with the anti-oxidant vitamin E may enhance NK cell function in cancer patients by protecting from oxidative stress. Seven patients with colorectal cancer (Dukes stage C and D) received a daily dose of 750 mg of vitamin E during a period of two weeks and the function, phenotype and receptor expression of NK cells were analyzed. The short-term vitamin E treatment significantly improved NK cell cytolytic activity in six out of the seven patients analyzed. The increased NK cell activity in patients' PBMC was not due to increased numbers of NK cells or an increase in the proportion of the CD56(dim) NK cell subpopulation. Furthermore, neither an increased perforin expression nor an enhanced ability of NK cells to produce IFN-gamma was observed as a result of vitamin E treatment. Finally, vitamin E treatment was associated with a minor, but consistent, induction of NKG2D expression in all patients analyzed. In conclusion, this pilot study demonstrates that vitamin E may boost NK cell function in patients with colorectal cancer. Further studies are warranted to explore the potential of vitamin E as an adjuvant for immunotherapy against cancer and to determine the underlying mechanism(s) behind vitamin E induced NK cell activation.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Loskog, Angelica, et al.
(author)
-
Dendritic cells engineered to express CD40L continuously produce IL12 and resist negative signals from Tr1/Th3 dominated tumors
- 2006
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 55:5, s. 588-597
-
Journal article (peer-reviewed)abstract
- TNFalpha-matured dendritic cells (DCs) pulsed with tumor antigens are being evaluated as cancer vaccines. It has been shown that DCs produce IL12 during a limited time span and subsequently enter a stage of IL12 exhaustion. If DCs are generated ex vivo, the patient could receive IL12-exhausted DCs which may be detrimental for stimulating anti-tumor Th1 responses. Furthermore, many cancer patients exhibit a cytokine profile skewed toward IL10 and TGFbeta. This immunological profile, called the Tr1/Th3 response, is associated with the presence of regulatory T-cells. Tr1/Th3 responses potently inhibit DC maturation, thereby regulating Th1 responses. In the present study, we produced genetically engineered DCs that continuously express Th1-related cytokines such as IL12, and resist negative signals from Tr1/Th3-dominated bladder carcinoma cells. Human immature DCs were genetically engineered by adenoviral vectors to express CD40L, or were treated with TNFalpha as a positive control for maturation. The expression of different Th1/Th3 and inflammatory cytokines was monitored. IL12 and IFNgamma were expressed by CD40L-engineered DCs, while TNFalpha-matured DCs lacked IFNgamma and exhibited low IL12 expression. The addition of recombinant IL10 to genetically engineered DCs did not abolish their Th1 profile. Likewise, coculture with tumor cell lines expressing TGFbeta with or without recombinant IL10 did not revert to the engineered DCs. We further demonstrate that the resistance of CD40L-expressing DCs to TGFbeta and IL10 may be due to decreased levels of TGFbeta and IL10 receptors. Thus, CD40L-engineered DCs are robust Th1-promoting ones that are resistant to Tr1/Th3-signaling via IL10 and TGFbeta.
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
- Miller, AM, et al.
(author)
-
Tumor escape mechanisms in prostate cancer
- 2007
-
In: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 56:1, s. 81-87
-
Journal article (peer-reviewed)
|
|
| 17. |
|
|
| 18. |
- Mozaffari, Fariba, et al.
(author)
-
Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer : a longitudinal study
- 2009
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 58:1, s. 111-120
-
Journal article (peer-reviewed)abstract
- Immunotherapy is being increasingly utilized for adjuvant treatment for breast cancer (BC). We have previously described immune functions during primary therapy for BC. The present study describes immune recovery patterns during long-term, unmaintained follow-up after completion of adjuvant therapy. A group of patients with primary BC had been treated with adjuvant radio-chemotherapy therapy (RT + CT) 5-fluorouracil, epirubicin and cyclo-phosphamide (FEC) (n = 21) and another group with radiotherapy (RT) (n = 20) alone. Immunological testing of NK and T-cell functions was performed initially at the end of adjuvant treatment and repeated after 2, 6 and 12 months. NK cell cytotoxicity was significantly higher (P < 0.05) at all time-points in patients than in age-matched controls and did not differ between the two treatments groups during one year observation. In contrast, lower numbers of CD4 T-cells and lower expression of CD28 on T-cells was observed particularly in RT + CT patients and did not normalize during the observation period. The numbers of T-reg cells (CD4(+) CD25(high)) were low in the RT + CT group during follow-up, as well as expression of TCR xi, Zap70, p56(lck), P59(fyn) and PI3 k in CD4+ cells. In contrast, expression of intracellular cytokines (IFN-gamma, IL-2, IL-4) in CD4 and CD8 T cells were signiWcantly higher in RT + CT patients than in the RT group and the difference increased during follow-up. In conclusion, NK-cell cytotoxicity increased during unmaintained long-term follow-up whereas CD4 and regulatory T cells as well as signal transduction molecules remained low following adjuvant radio-chemotherapy.
|
|
| 19. |
- Okroj, Marcin, et al.
(author)
-
Hypoxia increases susceptibility of non-small cell lung cancer cells to complement attack.
- 2009
-
In: Cancer immunology, immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 58, s. 1773-1782
-
Journal article (peer-reviewed)abstract
- The complement system can be specifically targeted to tumor cells due to molecular changes on their surfaces that are recognized by complement directly or via naturally occurring antibodies. However, tumor cells often overexpress membrane-bound complement inhibitors protecting them from complement attack. We have previously shown that non-small cell lung cancer (NSCLC) cells, additionally to membrane-bound inhibitors, produce substantial amounts of soluble regulators such as factor I (FI) and factor H (FH). Since low oxygen concentration is associated with rapidly growing solid tumors, we studied how NSCLC cells protect themselves from complement attack under hypoxic conditions. Unexpectedly, mRNA levels and secretion of both FI and FH were significantly decreased already after 24 h exposure to hypoxia while cell viability measured by XTT assay and annexin V/7-AAD staining was affected only marginally. Furthermore, we observed decrease of mRNA level and loss of membrane-bound complement inhibitor CD46 and increased deposition of early (C3b) and terminal (C9) complement components on hypoxic NSCLC cells. All three complement pathways (classical, lectin and alternative) were employed to deposit C3b on cell surface. Taken together, our results imply that under hypoxic conditions NSCLC give up some of their available defense mechanisms and become more prone to complement attack.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- van der Most, Robbert G., et al.
(author)
-
Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy
- 2009
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 1432-0851 .- 0340-7004. ; 58:8, s. 1219-1228
-
Journal article (peer-reviewed)abstract
- Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25(+) regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25(+) regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25(+) regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3(+) regulatory CD4(+) T cells. Ki-67(hi) CD4(+) T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25(+) CD4(+) T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
- Vikman, Sofia, et al.
(author)
-
CD8(+) T cells against multiple tumor-associated antigens in peripheral blood of midgut carcinoid patients
- 2008
-
In: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 57:3, s. 399-409
-
Journal article (peer-reviewed)abstract
- PURPOSE: The aim of the study was to identify immunogenic HLA-A*0201-binding epitopes derived from a number of classical midgut carcinoid-associated proteins. CD8(+) T cells recognizing tumor-associated antigen (TAA) epitopes are of great interest for the establishment of immunotherapy as a novel treatment for this type of malignancy. EXPERIMENTAL DESIGN: Midgut carcinoid tumor specimens were microdissected and expression levels of potential TAAs were investigated by quantitative real time PCR. HLA-A*0201-binding motifs were selected using HLA peptide binding prediction algorithms and stabilization of HLA-A*0201 was verified using TAP-deficient T2 cells. Peripheral blood of midgut carcinoid patients was analyzed for peptide epitope recognition and the feasibility of generating peptide-reactive CD8(+) T cells in healthy blood donors was examined by an in vitro stimulation protocol using mature DCs. Activation of patient and healthy donor CD8(+) T cells was analyzed by intracellular flow cytometry staining of interferon gamma. RESULTS: Chromogranin A (CGA), tryptophan hydroxylase 1 (TPH-1), vesicular monoamine transporter 1 (VMAT-1), caudal type homeobox transcription factor 2 (CDX-2), and islet autoantigen 2 (IA-2) are properly expressed by midgut carcinoid tumor cells, with CGA mRNA expressed to greatest level. Midgut carcinoid patients have increased frequencies of peripheral blood CD8(+) T cells recognizing a pool of HLA-A*0201 peptides derived from these proteins compared to healthy age-matched individuals. Activated peptide-specific CD8(+) T cells could also be generated in healthy blood donors by in vitro stimulation. CONCLUSION: We have identified a number of immunogenic midgut carcinoid-associated peptide epitopes recognized by CD8(+) T cells. We show that midgut carcinoid patients display immune recognition of their tumors. Memory CD8(+) T cells in patient blood are of great interest when pursuing an immunotherapeutic treatment strategy.
|
|
| 27. |
- Yang, Q., et al.
(author)
-
Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells.
- 2006
-
In: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 55:6, s. 699-707
-
Journal article (peer-reviewed)abstract
- We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique "compact" morphology compared to the "loose" morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1(+) vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1(+) vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.
|
|
| 28. |
|
|
