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

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 2

Antitumor efficacy of Ag-loaded monocytes relative to conventional DC vaccines.

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Antitumor efficacy of Ag-loaded monocytes relative to conventional DC va...
(A and B) Growth of SQ B16/F10-OVA melanoma tumors (2 × 105) in mice untreated (no treatment) or vaccine treated beginning 8 days after tumor inoculation. (A) Vaccines: 106 OVA-monocytes IV weekly × 3 (OVA-mono 3×) or 106 OVA RNA–DCs SQ weekly × 3 (OVA-DC 3×) with tetanus-diphtheria toxoid immunization (Td) and adoptive OT-I cell transfer (OT-I). (B) Vaccines: 3 × 106 OVA-monocytes IV × 1 (OVA-mono 1x), 106 OVA RNA-pulsed DCs SQ × 3 (OVA-DC 3×) + Td, or 106 OVA RNA-pulsed DCs SQ × 3 (OVA-DC 3×) + Td + OT-I. (C) Growth of SQ B16/F10 melanoma tumors (5 × 104) in mice untreated (no treatment) or vaccinated every other day beginning 2 days after tumor inoculation for 5 doses of SQ 106 TRP2180-188–loaded (250 μg/mL) DCs (TRP2-DC SQ), IV 106 TRP2180-188–loaded (250 μg/mL) DCs (TRP2-DC IV), IV 106 SIINFEKL-loaded monocytes (SIINFEKL-mono IV), or IV 106 TRP2180-188–loaded monocytes (TRP2-mono IV). Tumor size comparison: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (unpaired 2-tailed Student’s t test). (D) Frequency of TRP2-specific (TRP2180-188-H-2Kb tetramer+) CD8+ T cells among total blood CD8+ T cells on day 16 after tumor inoculation in the experiment of C. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (1-way ANOVA with Tukey’s test). (E) Survival of the mice IC inoculated with TRP2-expressing CT-2A astrocytoma cells (5 × 104) either untreated (no treatment) or treated with 5 doses of TRP2180-188–loaded DCs (TRP2-DC SQ or IV) or monocyte (TRP2-mono IV) vaccination every other day beginning on day 2 after tumor inoculation. Median, median survival days. Survival curve comparison: *P < 0.05, and **P < 0.01 (log-rank test). For A–E, n = 8 per group. Data represent mean ± SEM.