Regulation of the tumor immune microenvironment and vascular normalization in TNBC murine models by a novel peptide

Abstract

Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive disease with limited treatment options. Recently, the combination of the immune checkpoint inhibitor (ICI) atezolizumab (anti-PD-L1) with nab-paclitaxel was approved following a clinical trial that showed response rates in at least 43% of patients. While this approval marks a major advance in the treatment of TNBC it may be possible to improve the efficacy of ICI therapies through further modulation of the suppressive tumor immune microenvironment (TIME). Several factors may limit immune response in TNBC including aberrant growth factor signaling, such as VEGFR2 and cMet signaling, inefficient vascularization, poor delivery of drugs and immune cells, and the skewing of immune cell populations toward immunosuppressive phenotypes. Here we investigate the immune-modulating properties of AXT201, a novel 20 amino-acid integrin-binding peptide in two syngeneic mouse TNBC models: 4T1-BALB/c and NT4-FVB. AXT201 treatment improved survival in the NT4 model by 20% and inhibited the growth of 4T1 tumors by 47% over 22 days postinoculation. Subsequent immunohistochemical analyses of 4T1 tumors also showed a 53% reduction in vascular density and a 184% increase in pericyte coverage following peptide treatment. Flow cytometry analyses demonstrated evidence of a more favorable anti-tumor immune microenvironment following treatment with AXT201, including significant decreases in the populations of T regulatory cells, monocytic myeloid-derived suppressor cells, and PD-L1 expressing cells and increased expression of T cell functional markers. Together, these findings demonstrate immune-activating properties of AXT201 that could be developed in combination with other immunomodulatory agents in the treatment of TNBC.

The recent progress of myeloid‐derived suppressor cell and its targeted therapies in cancers

“…synthesized a RGD‐contained, lactate dehydrogenase A (LDHA) small inhibitory RNA‐cored nanostructure assembly, this specific assembly could inhibit LDHA expression, which subsequently decreased G‐CSF and GM‐CSF production and suppressed MDSC recruitment. Another peptide AXT201, a 20‐amino polypeptide, achieves antitumor effect by the reduction of protumor growth factors, such as VEGF, HGF, and insulin‐like growth factor 1, inhibition of angiogenesis, remodeling of the TME, and promotion of CD8 + T cell activation 284 . AXT201 was shown to mainly alter the proportion of MDSC subtypes in triple‐negative breast cancer to realize an antitumor change in the TME.…”

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies

“…Meanwhile, miR-155-5p antagonist also enhanced the antitumor effect of cetuximab in TNBC xenotransplantation model [ 347 ]. Cancer cells with anoikis resistance are prone to metastasis [ 348 ], which is reported to be related to integrin and growth factor receptor [ 349 – 354 ]. HPW-RX40, which inhibited integrin, combined with EGFR inhibitor AG1478, could inhibit FAK/paxillin phosphorylation and significantly induce TNBC cell death [ 297 ].…”

Development of an immune-related prognostic biomarker for triple-negative breast cancer

“…Importantly, the rapid expansion of tumour tissue induces hypoxia and necrosis, reprogramming the TIME gene expression landscape to radically affect immune cell survival, recognition, and anti-tumour function. In comparison to other breast cancers, the TIME in TNBC is associated with higher expression of vascular endothelial growth factors and other molecules promoting growth and migration of tumour cells, as well as tumour-infiltrating lymphocytes and tumour-associated macrophages [ 6 , 7 ]. It has been shown that the presence of tumour-infiltrating lymphocytes is correlated with a better prognosis and an improved response to neoadjuvant chemotherapy in TNBC [ 8–10 ].…”