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Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses
Min-Nung Huang, … , John H. Sampson, Michael D. Gunn
Min-Nung Huang, … , John H. Sampson, Michael D. Gunn
Published October 29, 2019
Citation Information: J Clin Invest. 2020;130(2):774-788. https://doi.org/10.1172/JCI128267.
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Research Article Immunology Vaccines

Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses

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Abstract

Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic CD8+ DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43–containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction–mediated Ag transfer pathway between monocytes and CD8+ DCs and suggest that administration of tumor Ag–loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers.

Authors

Min-Nung Huang, Lowell T. Nicholson, Kristen A. Batich, Adam M. Swartz, David Kopin, Sebastian Wellford, Vijay K. Prabhakar, Karolina Woroniecka, Smita K. Nair, Peter E. Fecci, John H. Sampson, Michael D. Gunn

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Figure 1

Ag-loaded monocytes induce robust CTL responses.

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Ag-loaded monocytes induce robust CTL responses.
(A) Frequency of OVA-sp...
(A) Frequency of OVA-specific (tetramer+) CD8+ T cells among total CD8+ T cells in the spleen on day 7 after IV injection of the indicated doses of OVA-monocytes. (B) Representative dot plots gated on live CD8+ T cells showing frequency of OVA-specific CD8+ T cells among total CD8+ T cells in the spleen on day 7 after SQ 200 μg OVA/CFA, IV OVA-monocytes (3 × 106; OVA-mono), or IV monocytes alone (Mono). (C) Frequency of OVA-specific CD8+ T cells derived from B. (D) Expression of cytotoxicity-related markers on splenic OVA-specific CD8+ T cells presented as MFI and percentages of marker-positive cells among OVA-specific CD8+ T cells on day 7 after SQ OVA/CFA, or IV OVA-mono. Eomes, eomesodermin; GZB, granzyme B. (E) In vivo CTL activity of splenocytes toward SIINFEKL-pulsed targeted cells (specific lysis) 7 days after SQ PBS/CFA, OVA/CFA and IV OVA-mono. (F) Representative dot plots showing frequency of TRP2-specific (tetramer+) CD8+ T cells among total blood CD8+ T cells 2 days after the last dose of 5 IV injections of TRP2180-188–monocytes (TRP2-mono) or unloaded monocytes (Mono) (106/injection, every other day). (G) Frequency of TRP2-specific CD8+ T cells derived from F. (H) Frequency of OVA-specific CD8+ T cells among total CD8+ T cells in the spleen on day 7 after the indicated OVA-loaded cellular vaccination. (I) Representative dot plots showing frequency of OVA-specific CD8+ T cells among total CD8+ T cells in the spleen and LN on day 7 after SQ or IV OVA-monocyte vaccination. (J) Frequency of OVA-specific CD8+ T cells derived from I. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. One-way ANOVA with Tukey’s test (A, C, E, H); 2-way ANOVA with Bonferroni’s test (D and J); and unpaired 2-tailed Student’s t test (G). Data represent mean ± SEM.
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