Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines

Sruthi Ravindranathan,Narasimhan Rajaram,Bhanu Prasanth Koppolu,Samantha L Kurtz,Sean G Smith,Haven N Frazier,Khue G Nguyen,David A Zaharoff

doi:10.1186/s13058-018-1054-3

Abstract

BackgroundAlthough metastasis is ultimately responsible for about 90% of breast cancer mortality, the vast majority of breast-cancer-related deaths are due to progressive recurrences from non-metastatic disease. Current adjuvant therapies are unable to prevent progressive recurrences for a significant fraction of patients with breast cancer. Autologous tumor cell vaccines (ATCVs) are a safe and potentially useful strategy to prevent breast cancer recurrence, in a personalized and patient-specific manner, following standard-of-care tumor resection. Given the high intra-patient and inter-patient heterogeneity in breast cancer, it is important to understand which factors influence the immunogenicity of breast tumor cells in order to maximize ATCV effectiveness.MethodsThe relative immunogenicity of two murine breast carcinomas, 4T1 and EMT6, were compared in a prophylactic vaccination-tumor challenge model. Differences in cell surface expression of antigen-presentation-related and costimulatory molecules were compared along with immunosuppressive cytokine production. CRISPR/Cas9 technology was used to modulate tumor-derived cytokine secretion. The impacts of cytokine deletion on splenomegaly, myeloid-derived suppressor cell (MDSC) accumulation and ATCV immunogenicity were assessed.ResultsMice vaccinated with an EMT6 vaccine exhibited significantly greater protective immunity than mice vaccinated with a 4T1 vaccine. Hybrid vaccination studies revealed that the 4T1 vaccination induced both local and systemic immune impairments. Although there were significant differences between EMT6 and 4T1 in the expression of costimulatory molecules, major disparities in the secretion of immunosuppressive cytokines likely accounts for differences in immunogenicity between the cell lines. Ablation of one cytokine in particular, granulocyte-colony stimulating factor (G-CSF), reversed MDSC accumulation and splenomegaly in the 4T1 model. Furthermore, G-CSF inhibition enhanced the immunogenicity of a 4T1-based vaccine to the extent that all vaccinated mice developed complete protective immunity.ConclusionsBreast cancer cells that express high levels of G-CSF have the potential to diminish or abrogate the efficacy of breast cancer ATCVs. Fortunately, this study demonstrates that genetic ablation of immunosuppressive cytokines, such as G-CSF, can enhance the immunogenicity of breast cancer cell-based vaccines. Strategies that combine inhibition of immunosuppressive factors with immune stimulatory co-formulations already under development may help ATCVs reach their full potential.

Highlights

Metastasis is responsible for about 90% of breast cancer mortality, the vast majority of breast-cancer-related deaths are due to progressive recurrences from non-metastatic disease
In the absence of irradiation, both 4T1.G-CSF− and naïve mice (4T1) and EMT6 cells effectively proliferated over the time observed in this study (24–96 h)
Our analysis found no significant difference in the ΔMFI values of Intracellular adhesion molecule-1 (ICAM-1) between 4T1 and EMT6 before and after irradiation (Table 1)

Summary

Introduction

Metastasis is responsible for about 90% of breast cancer mortality, the vast majority of breast-cancer-related deaths are due to progressive recurrences from non-metastatic disease. Current adjuvant therapies are unable to prevent progressive recurrences for a significant fraction of patients with breast cancer. Autologous tumor cell vaccines (ATCVs) are a safe and potentially useful strategy to prevent breast cancer recurrence, in a personalized and patient-specific manner, following standard-of-care tumor resection. Since only about 4% of the 265,000+ new patients with breast cancer are typically diagnosed with stage IV metastatic cancer, the vast majority of breast-cancer-related deaths are due to the recurrence and progression of breast cancers initially diagnosed at stages I–III. In an attempt to prevent tumor recurrence, approximately four out of every five patients with breast cancer receive adjuvant therapies such as chemotherapy, hormone therapy, and/or radiotherapy following tumor resection [2]. Strategies capable of more effectively and more safely preventing progressive breast cancer recurrences, after standard-of-care tumor resection, are urgently needed

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