The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach

Abstract

ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8(+) T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8(+)CD44(hi) memory T cells and CD8(+)CD44(hi)CD62L(lo) effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8(+) T cells, CD8(+)CD44(hi) T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.

Chronic alcohol consumption inhibits peripheral NK cell development and maturation by decreasing the availability of IL-15

“…In the melanoma-bearing mice, chronic alcohol consumption inhibits CD8 + memory T cell, especially tumor-specific memory, CD8 + T cell expansion [49]. IL-15/IL-15Ra (ATL-803) treatment can effectively restore CD8 + memory T cells in the alcohol-consuming and melanoma-bearing mice [50]. These results further support the notion that chronic alcohol consumption induces the IL-15 defect in the microenvironment.…”

Immunomodulatory effects of cytokine-induced expansion of cytotoxic lymphocytes in a mouse model of lupus-like disease

“…Dendritic cells are thus unlikely to be a confounding driver of N-803-exacerbated disease that can be reversed with CD8a-depleting antibody. However, as N-803 can promote secretion of interferon gamma (IFN-g) from CD8 T cells [31,39,59,60], and IFN-g can cause pathologic accumulation of T FH cells and GCs [61À63], the authors speculate that excess IFN-g production after N-803 or IL-2C therapy may provoke worse disease outcomes, a possibility the authors will continue to explore. Regardless of the mechanism by which CD8 T cells may aggravate disease measures in this model, it is interesting to note that the authors' results contrast with those obtained following therapeutic application of IL-2C to the B6 £ DBA/2 F1 cGVHD mouse model of lupus-like disease [29], in which IL-2C-stimulated CD8 T cells ameliorated disease.…”

“…Injections of IL-2C (IL-2 complexed with S4B6 anti-IL-2 antibody) or the IL-15 superagonist N-803 into C57BL/6 mice resulted in expansion of the NK cell and CD8 T-cell compartments, whereas Foxp3 + CD4 + T regulatory cell proportions remained relatively unchanged [38,39]. To determine if NK cell attrition in the bm12 model could be averted via cytokine-mediated expansion of the NK cell compartment, the authors treated C57BL/6 mice with IL-2C three times over a span of 6 days prior to initiation of the disease model.…”

Immunomodulatory effects of cytokine-induced expansion of cytotoxic lymphocytes in a mouse model of lupus-like disease

“…Dendritic cells are thus unlikely to be a confounding driver of N-803exacerbated disease that can be reversed with CD8-depleting antibody. However, as N-803 can promote secretion of IFN- from CD8 T cells 31,39,59,60 , and IFN- can cause pathologic accumulation of TFH cells and GCs [61][62][63] , we speculate that excess IFN- production after N-803 or IL-2C therapy may provoke worse disease outcomes, a possibility that we will continue to explore. Regardless of the mechanism by which CD8 T cells may aggravate disease measures in this model, it is interesting to note that our results contrast with those obtained following therapeutic application of IL-2C to the B6 × DBA/2 F1 cGvHD mouse model of lupus-like disease 29 , in which IL-2C-stimulated CD8 T cells ameliorated disease.…”

“…Disease-associated attrition of NK cells can be reversed with targeted cytokine treatment. Injections of IL-2C (IL-2 complexed with S4B6 anti-IL-2 antibody) or the IL-15 superagonist N-803 into C57BL/6 mice results in expansion of the NK-cell and CD8 T-cell compartments, while Foxp3 + CD4 + T regulatory cell proportions remained relatively unchanged 38,39 . To determine if NK-cell attrition in the bm12 model can be averted via cytokinemediated expansion of the NK-cell compartment, we treated C57BL/6 mice with IL-2C three times over a span of six days prior to initiation of disease model.…”