Double negative T cell-NK cell axis orchestrates antitumor immunity against triple negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is hard to treat because of the development of chemoresistance and metastasis. It is recently found that the combination of chemotherapy and immune checkpoint blockade can significantly improve TNBC treatment. However, the low response rate to immunotherapy greatly hampers the application of immunotherapy to TNBC. It is urgent to find new paradigms to improve immunotherapy for TNBC. We previously found that transferring thymocytes into Ja281 KO mice could inhibit E0771 TNBC formation. Herein, we further determine the underlying mechanism. We found that transferring splenocytes, CD4 +, or CD8 +T cells into the Ja281 KO mice could not induce antitumor immunity. Transferring thymic double-negative T (DN T) cells into the Ja281 KO mice could inhibit tumor formation. Treating the cell-transferred Ja281 mice with anti-TCRβ or anti-TCRγδ antibodies two days before tumor inoculation, E0771 TNBC grew in the anti-TCRβ treated mice but not anti-TCRγδ-treated mice. These results indicated that the cell transfer-induced antitumor immunity in Ja281 KO mice was mediated by TCRαβ +DN T cells. Transferring iNKT or MAIT KO DN T cells did not affect cell-transfer-induced antitumor immunity. Only NK cell depletion abrogated DN T transfer-mediated antitumor immunity by using an antibody to deplete NK or macrophage, suggesting that NK cells are essential for DN T-mediated antitumor immunity against E0771. Antibody depletion of the circulating transferred cells did not affect cell transfer-induced antitumor immunity, suggesting that the DN T cells mediating antitumor immunity are tissue-resident cells. Collectively, these data indicate that the DN T/NK cell axis orchestrates antitumor immunity against TNBC. Supported by Washington State University College of Pharmacy and Pharmaceutical Sciences Start-up funds