Role of B Cells and IL-27 in Breast Cancer Progression and Drug Resistance
Abstract
Estrogen receptor-positive (ER+) breast cancer (BCa) patients have good prognosis when treated with endocrine therapy, i.e., aromatase inhibitors (AI), anti-estrogen (AE) molecules or selective ER degraders (SERD). However, the efficacy of these therapies is limited due to development of resistance that eventually lead to disease progression to metastases and death. This proposal will address the question how the host immune system is hijacked by BCa cells for tumor progression and resistance to current endocrine therapies. The host immune system is critical for the destruction of invading pathogens and tumors. However, different mechanisms are employed by cancer cells to escape the immune destruction. For instance, a subset of tumor-infiltrating B lymphocytes (which in general are critical for the host immunity) may exist to promote BCa progression and/or endocrine therapy resistance, as suggested by our compelling preliminary data showing that in a mouse model of BCa, deficiency in B cells results in much delayed tumor growth. As also shown by our other preliminary data, B cells are the primary source of cytokine IL-27, raising the possibility that B cells function through IL-27. Prompted by these preliminary data, here we hypothesize that B lymphocytes are recruited into BCa tumors to produce IL-27 cytokine, which in turn promotes cancer progression and mediates endocrine therapy resistance. We also hypothesize that B cell-produced IL-27 upregulates two molecules, PD-L1 and CXCR3, to mediate the effect of B cells. We will test these hypotheses in three aims: In Specific Aim 1, we will address the role of IL-27-producing B cells in tumor progression using two different mouse models of BCa. We will also address whether IL-27 itself accelerates tumor growth and exacerbates resistance to endocrine therapy, such as Letrozole and Tamoxifen. In Specific Aim 2, we will address the mechanisms underlying the impact of B cells and IL-27 on BCa in mice, with emphasis on the role of PD-L1 and CXCR3. Particularly, we will address the anti-tumor effect by combined PD-L1- and CXCR3-blocking regimen. In Specific Aim 3, we will analyze the presence of IL-27-producing B cells in human BCa tissues. We will also address the tumor-intrinsic role of B cell and IL-27 in human BCa in vitro and in vivo. Our proposal will have sustained impact. Results from the proposed study will quickly advance our understanding of how BCa progress and develop resistance to endocrinal therapy. If our hypothesis is proven that B cells mediate the resistance, it is immediately important to test whether B cell-depleting regimen, such as rituximab, a Food and Drug Administration (FDA)-approved drug to treat B cell lymphoma, can be used together with endocrine therapy to eliminate resistant cells. In addition, immunotherapies are in clinical trials to treat BCa patients, and have about 15%-20% of response rates in triple-negative breast cancer (TNBC) patients, representing a significant improvement over the current lack of approved therapy for TNBC. If our proposed experiments yield data showing that anti-PD-L1 antibody and small molecule inhibitor of CXCR3 can combine to achieve significant effects in inhibiting tumor growth and drug resistance in mouse models, they will lay the foundation of combinatorial therapies that target PD-L1 and CXCR3 in BCa and possibly other cancer types.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810020
Entities
People
- Zhenming Xu
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio