Spontaneous CD4+ T Cell Responses against TRAG-3 in Patients with Melanoma and Breast Cancers

Cyclin B1 (CCNB1) is considered as a potential target for a cancer vaccine, as it is overexpressed in many malignant cells, while being transiently expressed in normal cells. To evaluate the CD4 T cell response to CCNB1, we derived T cell lines by multiple weekly rounds of stimulation with recombinant CCNB1 of T cells collected in healthy donors (long-term T cell assays). T cell lines were specific for 15 immunodominant peptides and derived preferentially from naive T cells. From 74 overlapping peptides, 20 peptides were selected for their broad specificity of binding to HLA class II molecules and included most of the immunodominant epitopes. They primed in vitro a large number of specific CD4 T cell lines in all the donors. Immunodominant epitopes were the most efficacious in long-term T cell assays, both in terms of number of specific T cell lines and number of responding donors. The 20 peptides were also submitted to short-term T cell assays using cells collected in healthy and cancer patients with the aim to evaluate the memory response. The recognized peptides differed from the immunodominant peptides and were part of the best promiscuous peptides. We also observed pre-existing CCNB1-specifc IgG Abs in both healthy and cancer donors. Long- and short-term T cell assays revealed that CCNB1 contained many CD4 T cell epitopes, which are differentially recognized by pre-existing naive and memory CD4 T cells. These observations are of value for the design of cancer vaccines.

Section: Discussionmentioning

confidence: 71%

The Tumor Antigen Cyclin B1 Hosts Multiple CD4 T Cell Epitopes Differently Recognized by Pre-Existing Naive and Memory Cells in Both Healthy and Cancer Donors

Chevaleyre

Benhamouda

Favry

et al. 2015

“…We and others have previously shown that CGA-derived epitopes that represent tumor-specific T cell targets (27), give rise to spontaneous Th1-type CD4 + T cells isolated either from PBLs or TILs of cancer patients (24,28). However, such spontaneous CD4 + T cell responses are found in patients with progressive disease, questioning their role in promoting potent antitumor CTL functions.…”

Section: Discussionmentioning

confidence: 83%

“…We have previously reported that two immunodominant epitopes derived from the two CGAs, TRAG-3 34-48 and NY-ESO-1 119-143, stimulate spontaneous CD4 + T cells in the majority of patients with NY-ESO-1-expressing and/or TRAG-3-expressing melanoma (21,23,24). Using in vitro stimulation with peptides, we have previously isolated TRAG-3-specific CD4 + T cell clones (i.e., clones 61/58, 62/3, and 62/8) and NY-ESO-1-specific CD4 + T cell clones (i.e., clones 30/79, 35/67, and 11/4) from PBLs of two MPs and two HDs.…”

Section: Resultsmentioning

confidence: 99%

Human Tumor Antigen-Specific Helper and Regulatory T Cells Share Common Epitope Specificity but Exhibit Distinct T Cell Repertoire

Fourcade¹,

Sun²,

Kudela³

et al. 2010

Self Cite

CD4+ regulatory T cells (Tregs) accumulate at tumor sites and play a critical role in the suppression of immune responses against tumor cells. In this study, we show that two immunodominant epitopes derived from the tumor Ags (TAs) NY-ESO-1 and TRAG-3 stimulate both CD4+ Th cells and Tregs. TA-specific Tregs inhibit the proliferation of allogenic T cells, act in a cell-to-cell contact dependent fashion and require activation to suppress IL-2 secretion by T cells. TRAG-3 and NY-ESO-1–specific Tregs exhibit either a Th1-, a Th2-, or a Th0-type cytokine profile and dot not produce IL-10 or TGF-β. The Foxp3 levels vary from one Treg clone to another and are significantly lower than those of CD4+CD25high Tregs. In contrast to NY-ESO-1–specific Th cells, the NY-ESO-1–specific and TRAG-3–specific Treg clonotypes share a common TCR CDR3 Vβ usage with Foxp3+CD4+CD25high and CD4+CD25− T cells and were not detectable in PBLs of other melanoma patients and of healthy donors, suggesting that their recruitment occurs through the peripheral conversion of CD4+CD25− T cells upon chronic Ag exposure. Collectively, our findings demonstrate that the same epitopes spontaneously stimulate both Th cells and Tregs in patients with advanced melanoma. They also suggest that TA-specific Treg expansion may be better impaired by therapies aimed at depleting CD4+CD25high Tregs and preventing the peripheral conversion of CD4+CD25− T cells.

“…We have cloned and sequenced the TCR CDR3␤ regions of each cross-reactive clone as previously reported (28,29) and described in Materials and Methods. Each of the two NY-ESO-1-specific CD4 ϩ T cell clones exhibited a distinct CDR3␤ region involving distinct V␤ and J␤ chains, named CDR3␤ 11/4 (SFYICSAQ-GLAYEQYFGPGTR:V␤2.1-NDN-J␤2.7) and CDR3␤ 30/79 (VYFCASSPGRVSLSGANVLTFG: V␤9-NDN-J␤2.6), respectively.…”

Section: Ex Vivo Detection Of Cross-reactive Tcr From Pbls Of Stage Imentioning

confidence: 99%

Cross-Reactive CD4+ T Cells against One Immunodominant Tumor-Derived Epitope in Melanoma Patients

Kudela¹,

Janjic²,

Fourcade³

et al. 2007

Self Cite

TCRs exhibit a high degree of specificity but may also recognize multiple and distinct peptide-MHC complexes, illustrating the so-called cross-reactivity of TCR-peptide-MHC recognition. In this study, we report the first evidence of CD4+ T cells recognizing the same tumor peptide-epitope from NY-ESO-1, in the context of multiple HLA-DR and HLA-DP molecules. These cross-reactive CD4+ T cells recognized not only autologous but also allogenic dendritic cells previously loaded with the relevant protein (i.e., the normally processed and presented epitope). Using clonotypic real-time RT-PCR, we have detected low frequencies of CD4+ T cells expressing one cross-reactive TCR from circulating CD4+ T cells of patients with stage IV melanoma either spontaneously or after immunization but not in normal donors. The maintenance of cross-reactive tumor Ag-specific CD4+ T cells in PBLs of cancer patients required the presence of tumor Ag/epitope in the context of the MHC molecule used to prime the Ag-specific CD4+ T cells. Our findings have significant implications for the optimization of TCR gene transfer immunotherapies widely applicable to cancer patients.