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

The carcinoembryonic Ag (CEA) is an attractive target for immunotherapy because of its expression proﬁle and role in tumor progression. To verify the existence of spontaneous anti-CEA CD4 (cid:1) T cells in lung cancer patients, we ﬁrst identiﬁed CEA sequences forming naturally processed epitopes, and then used the identiﬁed epitopes to test their recognition by CD4 (cid:1) T cells from the patients. We had previously identiﬁed CEA as an immunodominant epitope recognized by CD4 (cid:1) T cells in association with several HLA-DR alleles. In this study, we identiﬁed four additional subdominant CEA sequences (CEA 99–111 , CEA , CEA , and CEA 666–678 ), recognized in association with one or more HLA-DR alleles. Peptide-speciﬁc CD4 (cid:1) T cells produced proinﬂammatory cytokines when challenged with the native protein and CEA-expressing tumor cells, thus demonstrating that the identiﬁed CEA sequences contain naturally processed epitopes. However, CEA is expressed in the thymus and belongs to the CD66 family that comprises highly homologous molecules expressed on hemopoietic cells, raising concerns about tolerance interfering with the in vivo development of anti-CEA immunity. We thus tested the spontaneous reactivity to the identiﬁed epitopes of peripheral blood CD4 (cid:1) T lymphocytes from eight early-stage lung cancer patients bearing CEA-positive tumors. We found GM-CSF- and IFN- (cid:2) - producing CD4 (cid:1) T cells in