Immunotherapeutic target expression on breast tumors can be amplified by hormone receptor antagonism: a novel strategy for enhancing efficacy of targeted immunotherapy
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Ritika Jaini1,3,5, Matthew G. Loya1, Charis Eng1,2,3,4,5
1Genomic Medicine Institute, Lerner Research Institute, Cleveland, OH 44195, USA
2Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
3Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
4Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
5Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Ritika Jaini, email: firstname.lastname@example.org
Keywords: antigen amplification, tamoxifen, estrogen receptor antagonist, vaccine, cell-mediated immunotherapy
Received: December 23, 2016 Accepted: February 18, 2017 Published: March 01, 2017
Immunotherapy has historically been successful in highly antigenic tumors but has shown limited therapeutic efficacy in non-antigenic tumors such as breast cancers. Our previous studies in autoimmunity have demonstrated that increased antigen load within a tissue enhances immune reactivity against it. We therefore hypothesized that enhancing expression of target proteins on breast tumors can increase efficacy of targeted immunotherapy. We hypothesized that antagonism of the estrogen receptor (ER) can increase expression of targets that are hormonally regulated and facilitate enhanced tumor recognition by targeted immunotherapy. We used a lactation protein α-Lactalbumin, a known immunotherapeutic target on breast tumors, as our model target antigen. Enhancement of target protein expression in human and murine breast tumors was tested in vitro and in vivo by ER antagonism using clinically established ER modulators, Tamoxifen and Fulvestrant. We show that antagonism of the ER can induce a 2–3 fold increase in expression of target proteins on tumors leaving the normal breast tissue unaffected. Tumor progression studies in 4T1 tumor-bearing mice show that efficacy of adoptively transferred cell based targeted immunotherapy was enhanced by target antigen amplification resulting in significantly higher tumor inhibition. However, in spite of increased target expression, anti-tumor efficacy of direct immunization was not enhanced probably due to other limiting factors involved in the immune priming process. Our study provides a novel combinatorial clinical strategy for enhancing efficacy of immunotherapy not only on breast tumors but potentially also for other hormonally driven tumors such as those of the prostate, testis and ovary.
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