Immunotherapeutic target expression on breast tumors can be amplified by hormone receptor antagonism: a novel strategy for enhancing efficacy of targeted immunotherapy.

Ritika Jaini,Matthew G. Loya,Charis Eng

doi:10.18632/oncotarget.15812

Abstract

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.

Highlights

Immunotherapy has historically been successful in highly antigenic tumors such as melanomas but has mostly encountered failure in non-antigenic tumors such as breast cancers [1, 2]
Our study provides a novel strategy for enhancing efficacy of tumor immunotherapy by amplification of the target on tumors
We show for the first time that expression of certain target antigens on hormone receptor positive breast tumors can be amplified by modulation of their hormone receptor regulated transcriptional processes

Summary

Introduction

Immunotherapy has historically been successful in highly antigenic tumors such as melanomas but has mostly encountered failure in non-antigenic tumors such as breast cancers [1, 2]. In spite of high efficacy in murine models, targeted immunotherapeutic strategies have mostly failed to translate this efficiency to the antigenically heterogeneous patient population encountered in the clinic. It has been shown that tumors with high mutation load are more antigenic and show greater responses to immunotherapeutic intervention [4]. Our own work in the experimental autoimmune encephalomyelitis murine model for multiple sclerosis has shown that increased antigen load within tissue leads to enhanced autoimmune reactivity targeted against it [6]. Increased antigenicity is considered to be a prerequisite for effective immunotherapy, there are no clinically viable strategies currently available to address this key issue and enhance target antigen expression on tumors. Most current immunotherapies circumvent the problem of inadequate target antigen expression by restricting patient population selection

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Conclusion