Identification of Novel Subdominant Epitopes on the Carcinoembryonic Antigen Recognized by CD4+ T Cells of Lung Cancer Patients

Crosti, Mariacristina; Longhi, Renato; Consogno, Giuseppe; Melloni, Giulio; Zannini, Piero; Protti, Maria Pia

doi:10.4049/jimmunol.176.8.5093

Cited by 18 publications

(22 citation statements)

References 25 publications

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“…With the experimental system used, we found proliferation and/or cytokine released by CEA-reactive CD4 ϩ T cells in ϳ65% of normal donors. We previously (39) failed to detect spontaneous anti-CEA CD4 ϩ T cells in a small cohort of seven normal subjects: important differences between the two studies are the number of subjects tested and the culture conditions used. The importance of the culture conditions in monitoring of immune responses for both background and low frequency detection has been recently reported (49).…”

Section: Discussionmentioning

confidence: 99%

“…The Institutional Ethics Committee had approved the study protocol and informed consent was obtained from all donors before blood sampling and surgical resection. (40) as promiscuous HLA-DR binders (i.e., able to bind to several alleles) and previously shown to contain naturally processed epitopes (35,(37)(38)(39). Sequence 307-319 from influenza hemagglutinin (HA 307-319 ) (41) and sequence 280 -294 from Epstein-Barr nuclear Ag 2 (EBNA2 280 -294 ) (42) were selected to test antiviral immunity.…”

Section: Subjects and Tumor Samplesmentioning

confidence: 99%

“…Others (35-37) and we (38,39) previously reported that CEA contains naturally processed epitopes recognized by CD4 ϩ T cells from normal donors and colon and lung cancer patients.…”

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confidence: 99%

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Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Tassi

Gavazzi

Albarello

et al. 2008

The Journal of Immunology

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Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients’ sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80–90% of pancreatic carcinomas and contains epitopes recognized by CD4+ T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the anti-CEA and antiviral CD4+ T cell immunity. CD4+ T cells from 23 normal donors and 44 patients undergoing surgical resection were tested for recognition of peptides corresponding to CEA and viral naturally processed promiscuous epitopes by proliferation and cytokine release assays. Anti-CEA CD4+ T cell immunity was present in a significantly higher number of normal donors than pancreatic cancer patients. Importantly, whereas CD4+ T cells from normal donors produced mainly GM-CSF and IFN-γ, CD4+ T cells from the patients produced mainly IL-5, demonstrating a skew toward a Th2 type. On the contrary, the extent of antiviral CD4+ T cell immunity was comparable between the two groups and showed a Th1 type. The immunohistochemical analysis of tumor-infiltrating lymphocytes showed a significantly higher number of GATA-3+ compared with T-bet+ lymphoid cells, supporting a Th2 skew also at the tumor site. Collectively, these results demonstrate that Th2-immune deviation in pancreatic cancer is not generalized but tumor related and suggests that the skew might be possibly due to factor(s) present at the tumor site.

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Section: Discussionmentioning

confidence: 99%

Section: Subjects and Tumor Samplesmentioning

confidence: 99%

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Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Tassi

Gavazzi

Albarello

et al. 2008

The Journal of Immunology

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“…re-existing T cell responses to tumor-associated Ags (TAAs) 3 have been reported in patients with solid tumors, including melanomas, colorectal, lung, breast, ovarian, prostate, and pancreatic carcinomas (1)(2)(3)(4)(5). However, these responses usually involve a low frequency of T cells, and are not detected in the majority of patients, with the exception of melanoma (1,5,6).…”

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confidence: 99%

Functional T Cell Responses to Tumor Antigens in Breast Cancer Patients Have a Distinct Phenotype and Cytokine Signature

Inokuma

Rosa

Schmitt

et al. 2007

The Journal of Immunology

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The overall prevalence with which endogenous tumor Ags induce host T cell responses is unclear. Even when such responses are detected, they do not usually result in spontaneous remission of the cancer. We hypothesized that this might be associated with a predominant phenotype and/or cytokine profile of tumor-specific responses that is different from protective T cell responses to other chronic Ags, such as CMV. We detected significant T cell responses to CEA, HER-2/neu, and/or MAGE-A3 in 17 of 21 breast cancer patients naive to immunotherapy. The pattern of T cell cytokines produced in response to tumor-associated Ags (TAAs) in breast cancer patients was significantly different from that produced in response to CMV or influenza in the same patients. Specifically, there was a higher proportion of IL-2-producing CD8+ T cells, and a lower proportion of IFN-γ-producing CD4+ and/or CD8+ T cells responding to TAAs compared with CMV or influenza Ags. Finally, the phenotype of TAA-responsive CD8+ T cells in breast cancer patients was almost completely CD28+CD45RA− (memory phenotype). CMV-responsive CD8+ T cells in the same patients were broadly distributed among phenotypes, and contained a high proportion of terminal effector cells (CD27−CD28−CD45RA+) that were absent in the TAA responses. Taken together, these results suggest that TAA-responsive T cells are induced in breast cancer patients, but those T cells are phenotypically and functionally different from CMV- or influenza-responsive T cells. Immunotherapies directed against TAAs may need to alter these T cell signatures to be effective.

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“…CD4 + T cells were purified from total PBMCs and CBMCs by magnetic separation (Miltenyi Biotech) and cultured as described previously (27,28). Briefly, CD4 + T cells (5 Â 10 4 per well) were cultured in X-VIVO 15 medium (Biowhittaker) supplemented with 3% heatinactivated normal human serum (NHS), penicillin (100 units/mL), and streptomycin (50 Ag/mL; Biowhittaker; tissue culture medium) in the presence of irradiated CD4 + -depleted PBMCs as antigen-presenting cells (APC) at 1:3 ratio in 96-well plates in six replicates for each condition.…”

Section: Methodsmentioning

confidence: 99%

Endosomal Proteases Influence the Repertoire of MAGE-A3 Epitopes RecognizedIn vivoby CD4+ T Cells

et al. 2008

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Little is known about the repertoire of MAGE-A3 CD4 + T-cell epitopes recognized in vivo by neoplastic patients and how antigen processing influences epitope formation. Here, we first show that MAGE-A3-specific CD4 + T cells are present in the blood of advanced melanoma patients. MAGE-A3 111-125 , , and MAGE-A3 281-300 were recognized by 7, 6, and 5 of the 11 patients tested, respectively. MAGE-A3 146-160 and MAGE-A3 171-185 were also recognized in two and one cases, whereas no recognition of MAGE-A3 161-175 and MAGE-A3 243-258 was observed. Cytokines produced were mainly interleukin 5 and/or granulocyte macrophage colony-stimulating factor, suggesting impairment of productive polarized Th1 responses. Secondly, proteases inhibitors were used to modulate in vitro the recognition by CD4 + T-cells clones of dendritic cells loaded with MAGE-A3-expressing cell lysates. We found that formation of MAGE-A3 111-125 depended on both leupeptin-sensitive and pepstatin-sensitive proteases. In contrast, we found that MAGE-A3 161-175 , which was never recognized ex vivo, was formed by leupeptin but destroyed by pepstatin-sensitive proteases. Collectively, our results show that (a) anti-MAGE-A3 CD4 + T-cell immunity develops in vivo in neoplastic patients and is focused toward immunodominant epitopes, (b) the response in advanced disease is skewed toward a Th2 type, and (c) endosomal/lysosomal proteases in dendritic cells influence the repertoire of the epitopes recognized. [Cancer Res 2008; 68(5):1555-62]

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Identification of Novel Subdominant Epitopes on the Carcinoembryonic Antigen Recognized by CD4+ T Cells of Lung Cancer Patients

Cited by 18 publications

References 25 publications

Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Functional T Cell Responses to Tumor Antigens in Breast Cancer Patients Have a Distinct Phenotype and Cytokine Signature

Endosomal Proteases Influence the Repertoire of MAGE-A3 Epitopes RecognizedIn vivoby CD4+ T Cells

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