Abstract
The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer
Highlights
IL21 is a member of common g-chain family of cytokines that is produced mainly by natural killer T (NKT) cells and CD4þ T cells, with the highest production by T follicular helper (Tfh) cells and Th17 cells [1, 2]
It has been suggested that increasing levels of tumor-infiltrating lymphocytes (TIL) are associated with higher trastuzumab benefit on distant disease-free survival (DDFS) when added to chemotherapy in primary HER2þ breast cancer [36, 42]
We investigated the association between IL21 and IL21 receptor (IL21R) expression and trastuzumab efficacy on relative risk of distant recurrence in primary HER2þ breast cancers treated in a landmark randomized clinical trial evaluating the efficacy of trastuzumab in addition to standard chemotherapy [37] through the use of an interaction test
Summary
IL21 is a member of common g-chain family of cytokines that is produced mainly by natural killer T (NKT) cells and CD4þ T cells, with the highest production by T follicular helper (Tfh) cells and Th17 cells [1, 2]. IL21 can bind to IL21 receptor (IL21R), which is a heterodimer of IL21R and the common cytokine-g chain ( known IL2 receptor subunit gamma or IL2RG). Upon binding to IL21R, IL21 is able to exert its effects on a broad range of cell types, that includes but not limited to, the induction of apoptosis in dendritic cells IL21 is generally considered a proinflammatory cytokine, it can be immunosuppressive because of its ability to induce IL10 secretion from CD4þ and CD8þ T cells [21] and NK cells [11]
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