Type 2 dendritic cells mediate control of cytotoxic T cell resistant tumors
Stephen Iwanowycz, Soo Ngoi, Yingqi Li, Megan Hill, Christopher Koivisto, Melodie Parrish, Beichu Guo, Zihai Li, Bei Liu
Stephen Iwanowycz, Soo Ngoi, Yingqi Li, Megan Hill, Christopher Koivisto, Melodie Parrish, Beichu Guo, Zihai Li, Bei Liu
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Research Article Immunology

Type 2 dendritic cells mediate control of cytotoxic T cell resistant tumors

Abstract

Type 2 DCs (DC2s) comprise the majority of conventional DCs within most tumors; however, little is known about their ability to initiate and sustain antitumor immunity, as most studies have focused on antigen cross-presenting DC1s. Here, we report that DC2 infiltration identified by analysis of multiple human cancer data sets showed a significant correlation with survival across multiple human cancers, with the benefit being seen in tumors resistant to cytotoxic T cell control. Characterization of DC subtype infiltration into an immunotherapy-resistant model of breast cancer revealed that impairment of DC1s through 2 unique models resulted in enhanced DC2 functionality and improved tumor control. BATF3 deficiency depleted intratumoral DC1s, which led to increased DC2 lymph node migration and CD4+ T cell activation. Enhancing DC2 stimulatory potential by genetic deletion of Hsp90b1 (encoding molecular chaperon GP96) led to a similar enhancement of T cell immunity and improved survival in a spontaneous breast cancer model. These data highlight the therapeutic and prognostic potential of DC2s within checkpoint blockade–resistant tumors.

Authors

Stephen Iwanowycz, Soo Ngoi, Yingqi Li, Megan Hill, Christopher Koivisto, Melodie Parrish, Beichu Guo, Zihai Li, Bei Liu

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Figure 5

DC1 depletion improves DC2 migration and enhances T cell priming.

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DC1 depletion improves DC2 migration and enhances T cell priming. (A) Re...
(A) Representative histograms displaying CCR7 surface expression on tiDC2s at the end point (left). n = 12–13 per group, with 1 of 4 representative experiments shown (right). (B) Representative flow plot of dLN DCs (left) and quantification of the frequency of migratory DC populations (CD45+B220–MHCIIhiCCR7+CD11c+ cells) (right). n = 12–13 per group, with 1 of 4 representative experiments shown. (C) Representative flow plot of CD4+ T cells from the dLN (left) and quantification of the frequency of different CD4+ T cells (right). n = 8 per group, with 1 of 4 representative experiments shown. (D) Representative flow plots of tumor-infiltrating CD4+ and CD8+ T cells for expression of PD-1 and CD69 (left), and the quantification of the data (right). n = 4–5 per group. (E) Representative histogram showing expression of iNOS in TAMs, MFI inset (left), and quantification of data (right). n = 3–4 per group, with 1 of 2 representative experiments shown. Data are shown as mean SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (2-tailed unpaired t test).