Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer

Abstract

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.

Regression of Lung Cancer in Mice by Intranasal Administration of SARS-CoV-2 Spike S1

“…The viability of cells was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method with an in vitro toxicology assay kit from Sigma as described earlier [ 16 , 17 ]. It was used to measure mitochondrial activity.…”

“…The activity of lactate dehydrogenase (LDH) was measured using a lactate dehydrogenase activity assay kit (Sigma) as described earlier [ 16 , 17 , 18 ]. A volume from the MTT assay was used and plated in a 96-well plate.…”

“…Fragmented DNA was detected in situ by the terminal deoxynucleotide transferase (TdT)-mediated binding of 3′OH ends of DNA fragments generated in response to apoptotic signals, using a commercially available kit (TdT FragEL DNA Detection Kit) from Millipore Sigma (Burlington, MA, USA) as described earlier [ 16 , 17 , 18 ]. Coverslips containing A549 lung adenocarcinoma cells cultured to 70–80% confluence were fixed with chilled methanol (Fisher Scientific, Waltham, MA, USA) for an hour, followed by two brief rinses with sterile PBS.…”

Overexpression of Interleukin-8 and Interleukin-13 as potent immune markers associated with survival and dietary habits in esophageal squamous cell carcinoma

“…Higher level of IL12 was reported in the sera of non-small-cell lung cancer, prostate carcinoma and metastatic renal cell carcinoma patients as compared to healthy controls [27, 29]. But lower level of IL12 was reported in the serum of breast cancer patients when compared to healthy controls [30]. Higher level of IL12 was also reported in the serum of esophageal SCC patients as compared to controls [31].…”

Crohn’s disease and breast cancer: a literature review of the mechanisms and treatment

“…P40 monomers, members of the IL-12 family, have tumor-promoting effects, and IL-23 is directly and indirectly involved in the genesis, growth and metastasis of tumor cells. Ustekinumab reduces the risk of tumors by antagonizing IL-12/IL-23 and does not increase the risk of tumors in elderly patients [ 81 – 83 ]. UST was also found not to increase tumor risk in patients in a phase III IM-UNITI clinical trial [ 84 ].…”