Triple-negative
breast carcinoma (TNBC) is one of the most aggressive types of solid-organ
cancers. While
immune checkpoint blockade (ICB)
therapy has significantly improved outcomes in certain types of solid-organ
cancers, patients with immunologically cold TNBC are afforded only a modest gain in survival by the addition of ICB to systemic
chemotherapy. Thus, it is urgently needed to develop novel effective therapeutic approaches for TNBC. Utilizing the 4T1 murine model of TNBC, we developed a novel combination immunotherapeutic regimen consisting of intratumoral delivery of high-mobility group
nucleosome binding protein 1 (
HMGN1), TLR2/6
ligand fibroblast-stimulating
lipopeptide (FSL-1), TLR7/8 agonist (R848/
resiquimod), and CTLA-4 blockade. We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach. 4T1-bearing mice responded with significant
tumor regression and
tumor elimination to our therapeutic combination regimen. Mice with complete
tumor regressions did not recur and became long-term survivors. Treatment with
HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both
tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of
HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of
chemotherapy, radiation, or exogenous
tumor-associated
antigen(s).