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Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity
Yaron Carmi, … , Michael N. Alonso, Edgar G. Engleman
Yaron Carmi, … , Michael N. Alonso, Edgar G. Engleman
Published November 3, 2016
Citation Information: JCI Insight. 2016;1(18):e89020. https://doi.org/10.1172/jci.insight.89020.
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Research Article Immunology Oncology

Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity

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Abstract

BM-derived DC (BMDC) are powerful antigen-presenting cells. When loaded with immune complexes (IC), consisting of tumor antigens bound to antitumor antibody, BMDC induce powerful antitumor immunity in mice. However, attempts to employ this strategy clinically with either tumor-associated DC (TADC) or monocyte-derived DC (MoDC) have been disappointing. To investigate the basis for this phenomenon, we compared the response of BMDC, TADC, and MoDC to tumor IgG-IC. Our findings revealed, in both mice and humans, that upon exposure to IgG-IC, BMDC internalized the IC, increased costimulatory molecule expression, and stimulated autologous T cells. In contrast, TADC and, surprisingly, MoDC remained inert upon contact with IC due to dysfunctional signaling following engagement of Fcγ receptors. Such dysfunction is associated with elevated levels of the Src homology region 2 domain–containing phosphatase-1 (SHP-1) and phosphatases regulating Akt activation. Indeed, concomitant inhibition of both SHP-1 and phosphatases that regulate Akt activation conferred upon TADC and MoDC the capacity to take up and process IC and induce antitumor immunity in vivo. This work identifies the molecular checkpoints that govern activation of MoDC and TADC and their capacity to elicit T cell immunity.

Authors

Yaron Carmi, Tyler R. Prestwood, Matthew H. Spitzer, Ian L. Linde, Jonathan Chabon, Nathan E. Reticker-Flynn, Nupur Bhattacharya, Hong Zhang, Xiangyue Zhang, Pamela A. Basto, Bryan M. Burt, Michael N. Alonso, Edgar G. Engleman

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Figure 5

Broad blockade of protein tyrosine phosphatases enables activation of TADC and MoDC by alloIgG-IC.

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Broad blockade of protein tyrosine phosphatases enables activation of TA...
(A) Flow cytometric analysis of MHC II and CD86 expression on blood monocyte-derived DC (MoDC) and tumor-associated DC (TADC) treated with orthovanadate (Na3VO4) following overnight incubation with allogeneic C57BL/6 IgG-LMP tumor cell immune complexes (alloIgG-IC). Graphs show the percentages of DC expressing both MHC II and CD86. Statistical significance was determined by 2-way ANOVA with Sidak’s multiple comparisons test. (B) Western blot analysis of phosphorylated SHP-1 (pSHP-1) in BM-derived DC (BMDC), MoDC, and TADC. Shown is 1 representative experiment of 4 performed. (C) Histograms show pAkt levels in DC after 10 minutes of incubation with LMP tumor cells or allogeneic C57BL/6 IgG-LMP tumor cell immune complexes (alloIgG-IC) and with or without SHP-1/2 inhibitor. Dot plots show arcsinh ratios of pAkt in DC incubated for 10 minutes with alloIgG-IC over baseline levels obtained from tumor cell–stimulated DC. These data also appear in Figure 6F as a reference for comparison. Statistical significance for BMDC was assessed using Student’s t test with Welch’s correction. Statistical significance for MoDC and TADC was determined by 2-way ANOVA with Tukey’s multiple comparisons test. Graphs show the mean levels obtained in 1 representative experiment of 3 independently repeated experiments. *P < 0.05, ****P < 0.0001.

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