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

Autor: Danielle Harrington, Yonghong Wan, Alyssa Vito, Ana L. Portillo, Nader El-Sayes, Samuel T Workenhe, Ian P. MacFawn, Karen L. Mossman, Omar Salem, Ali A. Ashkar, Tullia C. Bruno, Brad H. Nelson, Katy Milne
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer therapy
QH301-705.5
medicine.medical_treatment
Population
Medicine (miscellaneous)
Triple Negative Breast Neoplasms
Kaplan-Meier Estimate
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
0302 clinical medicine
Lymphocytes
Tumor-Infiltrating
Low-dose chemotherapy
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Chlorocebus aethiops
medicine
Animals
Humans
Biology (General)
education
Immune Checkpoint Inhibitors
Vero Cells
Triple-negative breast cancer
Oncolytic Virotherapy
education.field_of_study
B-Lymphocytes
business.industry
Myeloid-Derived Suppressor Cells
Immunotherapy
Combined Modality Therapy
Immune checkpoint
Blockade
Oncolytic virus
Mice
Inbred C57BL
030104 developmental biology
030220 oncology & carcinogenesis
Myeloid-derived Suppressor Cell
Cancer research
Female
General Agricultural and Biological Sciences
business
Zdroj: Communications Biology
Communications Biology, Vol 4, Iss 1, Pp 1-19 (2021)
ISSN: 2399-3642
Popis: 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.
Vito et al. investigated the effects of combination therapy in a TNBC tumor model and reported increased tumor-infiltrating lymphocytes that contributed to an improved response to immune checkpoint blockade. By depletion of circulating B cells prior to therapy, the authors showed a loss of therapeutic efficacy and simultaneous expansion of myeloid-derived suppressor cells.
Databáze: OpenAIRE
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