Project 3: Mechanisms of Immune Evasion in Breast Cancer
Yang-Xin Fu, MD, PhD
Rita Nanda, MD
The HER2/neu (HER2) gene is a member of a family of oncogenes implicated in cell proliferation. Its amplification has been implicated in 25% of breast cancers. Trastuzumab, an anti-HER2 antibody, is reported to mediate tumor regression by interrupting oncogenic signals. While some human tumors can be eradicated with anti-HER2-based therapy, other tumors relapse after initial response or fail to respond at all. The mechanisms of both de novo and acquired resistance are unclear. Using a mouse model, we have recently demonstrated that the therapeutic effect of anti-HER2 antibody therapy largely depends on T cell and IFN responses. Intriguingly, increased IFN in inflamed tumor tissue induces PD-L1 upregulation on inflamed cells that prevents further tumor destruction by T cells. This is one of the major immune evasion mechanisms after an initial tumor responses, Anti-PD-1 antibody treatment has been shown to have a response rate of up to 40% in patients with PD-L1 positive tumors, but has no effect in patients with PD-L1 negative disease. We hypothesize that anti-HER2 antibody treatment not only induces local inflammation that triggers tumor fighting immune responses, but also paradoxically increases negative signaling that suppresses local immunity via upregulation of PD-L1. We believe that trastuzumab-mediated PD-L1 upregulation suppresses the subsequent T cell killing of tumor cells, which leads to antibody resistance. Therefore, blockade of PD-L1-mediated immune suppression will synergize with anti-HER2 antibody therapy for better outcomes for patients with HER2-amplified breast cancer.
1. Understand mechanisms of resistance to anti-Her2/neu
1.1. To determine if and when PD-L1 is upregulated after anti-neu treatment. We will determine which cells express PD-L1 (dendritic cells or tumor cells), and determine whether PD-1 on T cells is upregulated before and after exposure to anti-neu antibody therapy and chemotherapy.
1.2. To determine whether anti-PD-L1 antibody treatment can increase tumor regression and reduce relapse after anti-neu antibody treatment.
1.3. To determine if anti-PD-L1 antibody can enhance anti-tumor immunity by killing or suppressing MDSCs.
1.4. To determine whether targeting PD-1 pathway by bi-specific antibody (anti-neu linked to anti-PD-L1) is superior to that by either anti-neu or anti-PD-L1 alone. Targeting tumor tissue with such novel bi-specific Ab would likely increase their synergy on their targets inside tumor tissues, which might be superior to co-administration of two individual antibodies.
1.5. To study how the immune system can be activated in a HER2/neu-dependent spontaneous tumor model that is more close to clinical tumor under single or combined treatment.
2. Understand the role that PD-L1 upregulation plays in resistance to trastuzumab-based therapy in patients with HER2-amplified breast cancer
2.1. To determine the proportion of HER2-amplifed breast tumors which have PD-L1 overexpression.
2.2. To determine the extent to which trastuzumab-based therapy can induce expression of PD-L1.
2.3. To correlate PD-L1 expression with pathological complete response in patients treated with neoadjuvant trastuzumab-based therapy for HER2-amplified breast cancer.
Impact on breast cancer outcome. Almost 60,000 women are diagnosed with HER2-amplified breast cancer annually in the United States alone. While trastuzumab had improved the outlook for women with early stage disease, a significant subset will relapse after adjuvant therapy, and those who present with de novo metastatic disease either fail to respond or eventually become resistant to HER2-directed therapy. While the recently approved pertuzumab and T-DM1 offer incremental improvements for patients with advanced breast cancer, resistance eventually emerges, and patients inevitably succumb to this deadly disease. Innovative treatment approaches that can dramatically improve outcomes for women with intrinsic or acquired resistance to HER2-directed therapy are urgently needed. Understanding the role of the PD-1/PD-L1 pathway in trastuzumab resistance warrants further investigation, as the combination of trastuzumab and PD-1/PD-L1 pathway inhibitors could represent a novel approach to improve outcomes for patients with this aggressive form of breast cancer.