Tumor-associated antigens identified early in mouse mammary tumor development can be effective vaccine targets

Original Articles
Sasha E. Stanton, Ekram Gad, Lauren R. Corulli, Hailing Lu, Mary L. Disis
Description / Abstract: 

Breast cancer vaccines composed of antigens identified by serological analysis of cDNA expression
libraries (SEREX) induce antigen specific immune responses in patients but have had disappointing clinical
benefits. While many attempts to modify the adjuvants and vaccine method have been tried, one
issue not addressed was whether the SEREX tumor-associated antigens identified from late stages of disease
were ideal targets. We questioned in the transgenic TgMMTV-neu mouse model whether the antigen
repertoire is distinct between early and late stage breast cancer and whether the antigens identified via
SEREX from transgenic mice with early or late stage tumors would elicit differential anti-tumor effects to
address this question.
Three early stage antigens, Pdhx, Stk39, and Otud6B, were identified from a SEREX screen of mice prior
to development of palpable lesions. Formulated into a vaccine, each early antigen inhibited tumor growth
(p < 0.0001). The antigens identified from mice with late stage tumors (Swap70, Gsn, and Arhgef2) were
unable to inhibit tumor growth when used as vaccines (for example Gsn p = 0.26). Each of the three early
stage antigens were essential for tumor survival in syngeneic mouse tumor cells and in human breast
cancer cell lines across breast cancer subtypes. Silencing protein expression of the early antigens
increased apoptosis (p < 0.0001 for all antigens in mouse and p < 0.05 for all antigens in human triple
negative breast cancer) and decreased survival (p < 0.0001 for all antigens in mouse and human triple
negative and HER2 positive breast cancer). Overexpression of the early stage antigens in women with
breast cancer predicted worse prognosis (p = 0.03) while overexpression of late stage antigens did not
impact prognosis (p = 0.09). These data suggest that antigens expressed earlier in breast tumor development
and functionally relevant to breast tumor growth may be more