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

Alyssa Vito,Brad H Nelson,Ian P Macfawn,Karen L Mossman,Yonghong Wan,Ali A Ashkar,Nader El-Sayes,Katy Milne,Ana L Portillo,Omar Salem,Samuel T Workenhe,Tullia C Bruno,Danielle Harrington

doi:10.1038/s42003-021-02375-9

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.

Highlights

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens
While chemotherapies are often given in dosedense cytotoxic regimens, many studies have described the immunostimulatory properties of various chemotherapeutics through the use of low-dose intervention[23,24,25,26]
In an effort to reverse translate these regimens from the clinic into murine models, we performed optimization studies to find dosing levels and schedules that showed no acute cytotoxicity to murine hosts, as determined through close monitoring of body weights and scoring (Supplementary Fig. 1)

Summary

Introduction

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. 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. A phase III clinical trial has shown that chemotherapy works to enhance the antitumor activity of CP in metastatic TNBC patients[3] This combination of chemotherapy and immunotherapy only confers a modest overall survival benefit[3]. Using a chemotherapy cocktail that is routinely used for TNBC patients will allow for ease of translation and biological analysis of current clinical applications

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