Distinct patient responses to activation of T-cells by free HER-2, G89 (777-789) and protected LRMK-linked HER-2, {AE-39 [p776 (Ava-774-788)], AE-47 [(Ava-776-788)] and AE-37[p776 (774-788)]} peptides could lead to development of personalized cancer vaccines.
The objective of this study was to find whether the peptide LRMK linked to the N-terminus of HER-2, 774-788 and shorter peptides create a T helper antigen, which can replace all functional HER-2 peptides in a cancer vaccine. Of the 6 LRMK-HER-2 peptides tested in the presence of IL-12, AE-37, AE-38 and AE-39 induced higher IFN-gamma in PBMCs from 4 healthy donors than the other peptides. AE-37 and AE-39 contained the immunogenic HER-2 peptide, p776 (774-788), while AE-38 contained the truncated HER-2 peptide G89 (777-788). The free, unprotected HER-2 peptide G89 (777-789) activated IFN-gamma production in PBMCs from another BRC patient. Responses to free p776 and F7 could not be tested. Three out of 11 patients responded strongly only to AE-37, while 3 of 10 patients responded strongly only to G89. One responded only to AE-39. All 3 patients diagnosed with DICS of mixed HER(hi), ER+ PR+ type responded to AE-37. Three out of 4 patients diagnosed with luminal cancer and one HERhi, ER- PR- BRC patient responded only to G89. AE-37, at low concentration, helped to expand more E75-TCR(Hi+Med) cells than the negative control AE-47, for IFN-gamma induction AE-47, but was a weaker helper than AE-47 at higher concentrations, and eliminated E75-TCR(Hi) cells. The strongest and most consistent effect of AE-37 was the elimination of CD4(Hi) CD25(Hi) cells. When LRMK is linked to AE-37, the side-chains of L(P-10) and R(P-9) are positioned away from MHC; LRMK forms a bi-strophynx (rotating-double-hook-like) structure when attached to AE-37 and the minimum HER-2 peptide in the peptide-binding groove (PBG). K(P-8) anchors the bi-strophynx to HLA-DR outside the PBG in a novel site DRalpha, 49-52. The HER-2 amino acids, Y(P-1) and R(P3) point towards TCR; R(P-9) and M(P-8) can contact the TCRValpha1. The positions of K(P-8) in AE-37 and Ava (epsilonV)(P-8) in AE-39 modulated immunogenicity of p776. It is unknown whether LRMK adds TCR contact points to the minimal HLA-DR-bound HER-2 peptide (780-788) or activates T-cells of other specificities to produce cytokines and die. Preferential activation of Th1 cells in distinct individuals by AE-37, G89 and AE-39 indicates that cancer vaccines will benefit from correct individual and disease-associated help. Emergence of distinct daughters of luminal and myoepithelial BRC stem cells during metastasis through "de-differentiation" and "reverse differentiation" of drug-resistant cancer requires personalized vaccines, which use an optimal-helper antigen.
Li
Yufeng
Y
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Matsueda
Satoko
S
Efferson
Clayton L
CL
Tsuda
Naotake
N
Kawano
Kouichiro
K
Gao
Hui
H
Peoples
George E
GE
Ioannides
Constantin G
CG