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 7

GP96 KODCs display enhanced T cell priming and maintenance.

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GP96 KODCs display enhanced T cell priming and maintenance. (A) Represen...
(A) Representative plot showing DCs from the draining LN of 18-week-old mice (left), and quantification of the frequency of migratory DC populations (CD45+B220–MHCIIhiCCR7+CD11c+ cells) (right). n = 6 per group. (B) Representative plot showing CD44 and CD62L expression in CD4 (top) and CD8 (bottom) T cells from the dLN of 18-week-old mice, and quantification of data (left). n = 6 per group. (C) Representative plot showing PD-1 and IFN-γ expression on tumor-infiltrating CD4 (left) and CD8 (middle) T cells from 18-week-old mice, along with quantification of data (right). T cells were stimulated with PMA and ionomycin for 4 hours before staining. n = 4 per group. (D) Representative flow plots of TNF-α– and IFN-γ–producing cells in tumor-infiltrating CD4 (top) and CD8 (bottom) T cells at the end point (24- to 28-week-old mice) (left). Quantification of data (right). T cells were stimulated with PMA and ionomycin for 4 hours before staining. n = 3–4 mice per group. (E) Representative plot showing tumor-infiltrating macrophages expression of CD86 and MHCII (left), and quantification of data (right). Data shows graph of M1-like polarization (CD86+). n = 8 to 9 mice/group. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (2-tailed unpaired t test).