Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells

Abstract

The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2þ 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 þ 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 þ 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 Res; 76(2); 264-74. Ó2016 AACR.

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

“…Beyond the activation of CD8 + T cells, IL-21 can suppress Tregs (42)(43)(44). In contrast, IL-2, a cytokine widely evaluated in preclinical and clinical studies, promotes both CD8 + T cells and Tregs (45)(46)(47).…”

Correlations Between Known Prognostic Markers and Tumor - infiltrating Lymphocytes in Breast Cancer

“…The analysis of TILs in relation to the histological differentiation (G) revealed the ascension between low TILs presence and poorly differentiated histological grade (G3), also supported by the study by Hee Jin Lee et al, 2015. [7] The Ki-67 proliferation index is one of the major prognostic factors in breast cancer, independent of the status of the axillary lymph. [8][9][10][11][12][13][14] Its role as a predictive factor in establishing the neoadjuvant and adjuvant treatment is controversial due to the conflicting results obtained in various studies.…”

Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy

“…We and others showed that CD8 + T cells and IFN-γ were required for the anti-ErB2 mAb therapy. 1,3,4 In order to test whether CD8 + T cells and IFN-γ are also required for BsPD-L1xrErbB2 therapy, we depleted either CD8 + T cells or CD4 + and CD8 + T cells together, or neutralized mouse IFN-γ in the groups of mice treated with bispecific control Ig (B12), anti-PD-L1 and anti-ErbB2 combination therapy and BsPD-L1xrErbB2 therapy. As shown before, bispecific antibody therapy induced more tumor rejections compared to the anti-PD-L1 and anti-ErbB2 combination therapy group.…”

“…Rat ErbB2-positive H2N100 tumor cells were generated from female Balb/c MMTV-ErbB2/neu transgenic mice and cultured as described previously. 1,29 TUBO cells were cultured in complete DMEM supplemented with 10% heat-inactivated fetal calf serum (Thermo Scientific), 1X glutamax, 50 U/ml penicillin, 100 μg/ml streptomycin and 10 mM HEPES (Sigma-Aldrich), while other cell lines were cultured in RPMI supplemented with 10% heat-inactivated fetal calf serum, 1X glutamax, 50 U/ml penicillin, 100 μg/ml streptomycin, 1 mM sodium pyruvate from Gibco-Life Technologies and 10 mM HEPES, 1% non-essential amino acid solution, and incubated at 37°C in 5% CO 2 incubator. The anti-rat ErbB2 mAb (clone 7.16.4) hybridoma was kindly provided by Mark I. Greene (University of Pennsylvania, Philadelphia, PA).…”

“…Its mechanism of action also builds on several innate and adaptive immune factors such as type I and II IFNs, IL-21, CD11b + and F4/80 + myeloid cells, NK cells, CD4 + and CD8 + T lymphocytes in ErbB2 + mouse models of breast cancers. [1][2][3][4] Some patients are refractory to trastuzumab treatment. 5 In addition to tumor cell-intrinsic factors such as downregulation of cell surface Her2 or mutations in the Her2-mediated PI3-kinase/AKT signaling pathways, 5 upregulation of immunosuppressive molecules such as PD-1 ligand, PD-L1 and adenosine generating CD73 are associated with trastuzumab resistance.…”