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.
Highlights
Accepted: 8 January 2022Breast cancer is the most common female cancer worldwide and the second most common cause of cancer-related deaths in women in USA [1]
We have seen that the level of p40 is much higher in the seru cancer patients as compared to healthy controls [4]
Earlier we demonstrated that p40 mAb a3-3a neutralized the production of nitric oxide and tumor tumor necrosis and necrosis factor factor αα (TNFα)
Summary
Accepted: 8 January 2022Breast cancer is the most common female cancer worldwide and the second most common cause of cancer-related deaths in women in USA [1]. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is characterized by the deficiency of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor. TNBC affecting younger women with a poor prognosis accounts for about 15–20% of all breast cancer. While tremendous advances have been made in other subtypes of breast cancer such as HER2+ tumors with the development of targeted agents against the HER2 receptor and ER+ breast cancers with agents to block estrogen signaling, there are no approved targeted treatments for TNBC. IL-12 family of cytokines has four different members including p40 monomer (p40), p40 homodimer (p402 ), IL-12 (p40:p35), and IL-23 (p40:p19) [4–11]. We have delineated that p40 is different from other IL-12 family members to selectively inhibit
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