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 3

Loss of DC1 restores immune control of breast tumors.

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Loss of DC1 restores immune control of breast tumors. (A) Growth of PyMT...
(A) Growth of PyMT breast tumors in C57BL/6 (WT) and Batf3–/– mice. Tumor area (left) is from 1 representative experiment of 4 total. Tumor weight (right) is pooled results from all 4 experiments, WT (n = 20), and KO (n = 16). (B) Tumor growth of EO771 breast tumor implanted into fourth mammary gland in WT and Batf3–/– mice. Tumor area (left) and tumor weight (right), n = 4 mice per group. (C) Tumor growth of B16-F1 melanoma implanted s.c. in WT and Batf3–/– mice. Tumor area (left) and tumor weight (right), n = 5 to 6 mice per group. (D) Tumor growth of MC38 colon tumor implanted subcutaneously. Tumor area (left) and tumor weight (right), n = 5–6 mice per group. (E) Frequency of tumor-infiltrating T cells analyzed at end point. Representative plot displaying CD45+CD11b–NK1.1–CD3+ cells. (F) Frequency of tumor-infiltrating immune cell populations, analyzed at the end point. Data displayed are from 1 of 4 trials, n = 4. (G) Histograms of surface expression (MFI) of indicated receptors (left) on tiDCs (CD45+B220–CD11c+MHCII+). The bar graph (right) is the tiDC2 phenotype for expression of indicated markers from WT and Batf3–/– mice. Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. (A, B, C, and D were analyzed by 2-way ANOVA for tumor growth; quantification was analyzed by 2-tailed unpaired t test).