Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells

Abstract

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.

Response to FEC Chemotherapy and Oncolytic HSV-1 Is Associated with Macrophage Polarization and Increased Expression of S100A8/A9 in Triple Negative Breast Cancer

“…While neither therapy showed as much of an effect on tumor growth as the monotherapy approach did, the mice treated with the dual combination of FEC + oHSV-1 had delayed tumor progression and 10–20% durable responses to treatment ( Figure 1 ). These data are consistent with our previously published findings using this therapeutic combination [ 12 ].…”

“…Asper our previous publications, microarray analysis showed that FEC + oHSV-1 therapy increased the genes associated with the B cell receptor signaling pathways. Of the top 100 genes from the B cell signature gene list that we previously published [ 12 ], 64 overlapped with the current dataset ( Table S1 ).…”

“…The accumulation of MDSCs in breast tumors is largely driven by cytokine and chemokine production and can influence the differentiation of TAMs to more suppressive phenotypes [ 37 ]. Additionally, B cells are known to be drivers of myeloid cell differentiation and key influencers of the cytokine and chemokine secretome in the TME [ 12 , 14 , 15 ]. While we often talk about cells of the myeloid lineage as being static cell types, it is important to remember that they are dynamic, plastic, and consistently undergoing differentiation.…”

“…Asper our previous publications, microarray analysis showed that FEC + oHSV-1 therapy increased the genes associated with the B cell receptor signaling pathways. Of the top 100 genes from the B cell signature gene list that we previously published [12], 64 overlapped with the current dataset (Table S1). Consistent with FEC + oHSV-1 therapy achieving durable responses in 10-20% of treated mice (Figure 1C and [11]), the transcriptomic profiling of the FEC + oHSV-1-treated mice shows that 80% of the mice clustered more similarly to the PBS-treated mice, with 20% of the mice having a distinct expression profile (Figure 2D).…”

“…We have previously reported an immunotherapy platform targeting immune-bare triple-negative breast cancer (TNBC) tumors using a clinical chemotherapy cocktail (FEC; 5-fluorouracil, epirubicin, cyclophosphamide) in combination with an oncolytic Herpes Simplex virus type 1 (oHSV-1) [ 12 ]. In this work, we showed that FEC + oHSV-1 therapy sensitized tumors to immune checkpoint blockade (ICB) and the requirements of tumor-infiltrating B cells to combat MDSC-driven immunosuppression in the TME.…”