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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 7

Activation of human MoDC by alloIgG-IC is regulated by both SHP-1 and calcium signaling.

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Activation of human MoDC by alloIgG-IC is regulated by both SHP-1 and ca...
(A) Proliferative response of CD4+ T cells from mesothelioma (MSTO) patients after 6-day culture with autologous BM monocyte-derived DC (BMDC), blood monocyte-derived DC (MoDC), or tumor-associated DC (TADC) and with self-IgG- or alloIgG-coated autologous tumor cells (self-IgG-IC or alloIgG-IC, n = 2). (B) Uptake by autologous DC of CFSE-labeled MSTO tumor cells (green) that were untreated or coated with allogeneic IgG (alloIgG-IC, 1 μg per 1 × 105 cells) (n = 2). Original magnification, ×40. (C) Proliferative response of CD4+ T cells from healthy donors after 6-day culture with autologous DC preactivated with tumor cells that had been incubated or not with intravenous Ig (IVIG, n = 5). (D) Uptake by MoDC from healthy donors of CFSE-labeled A549 tumor cells (green) incubated with allogeneic IgG (1 μg per 1 × 105 cells). Photomicrographs show 1 representative donor of 6 tested. Original magnification, ×40. (E) The effect of phosphatase inhibitors on the uptake of CFSE-labeled IC by MoDC from healthy donors (n = 4). (F) Mean fluorescence intensity (MFI) of CD86 and MHC II on MoDC following overnight incubation with alloIgG-IC in the presence or absence of phosphatase inhibitors (n = 4). Histograms show the mean levels obtained in 1 representative experiment of 4 independently repeated experiments. Statistical significance was determined by 2-way ANOVA with Sidak’s multiple comparisons test. **P < 0.01, ***P < 0.001, ****P < 0.0001.

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