Targeting the NANOG/HDAC1 axis reverses resistance to PD-1 blockade by reinvigorating the antitumor immunity cycle
Se Jin Oh, … , Marcus W. Bosenberg, Tae Woo Kim
Se Jin Oh, … , Marcus W. Bosenberg, Tae Woo Kim
Published February 1, 2022
Citation Information: J Clin Invest. 2022;132(6):e147908. https://doi.org/10.1172/JCI147908.
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Research Article Oncology

Targeting the NANOG/HDAC1 axis reverses resistance to PD-1 blockade by reinvigorating the antitumor immunity cycle

Abstract

Immune checkpoint blockade (ICB) therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses because of the emergence of immune-refractory tumors that disrupt the amplification of antitumor immunity. Therefore, the identification of clinically available targets that restrict antitumor immunity is required to develop potential combination therapies. Here, using transcriptomic data on patients with cancer treated with programmed cell death protein 1 (PD-1) therapy and newly established mouse preclinical anti–PD-1 therapy–refractory models, we identified NANOG as a factor restricting the amplification of the antitumor immunity cycle, thereby contributing to the immune-refractory feature of the tumor microenvironment (TME). Mechanistically, NANOG induced insufficient T cell infiltration and resistance to CTL-mediated killing via the histone deacetylase 1–dependent (HDAC1-dependent) regulation of CXCL10 and MCL1, respectively. Importantly, HDAC1 inhibition using an actionable agent sensitized NANOGhi immune-refractory tumors to PD-1 blockade by reinvigorating the antitumor immunity cycle. Thus, our findings implicate the NANOG/HDAC1 axis as a central molecular target for controlling immune-refractory tumors and provide a rationale for combining HDAC inhibitors to reverse the refractoriness of tumors to ICB therapy.

Authors

Se Jin Oh, Hyo-Jung Lee, Kwon-Ho Song, Suyeon Kim, Eunho Cho, Jaeyoon Lee, Marcus W. Bosenberg, Tae Woo Kim

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Figure 2

CT26 P3 cells display the immune-refractory feature of the TME.

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CT26 P3 cells display the immune-refractory feature of the TME. (A–I) CT...
(A–I) CT26 P0, P3, or N3 tumor–bearing mice were treated with IgG or anti–PD-1 (α–PD-1) antibody. (A) Tumor growth curves and (B) changes in tumor volume 17 days after challenge compared with baseline. CR, complete response. (C) Formalin-fixed, paraffin-embedded (FFPE) sections of CT26 P0 or P3 tumors treated with IgG or anti–PD-1 antibody were stained with the indicated markers by pseudo-coloring. The indicated markers are shown on the right. Scale bars: 100 μm and 20 μm (enlarged insets). (D) Frequency of tumor-infiltrating CD8+ T cells. (E) Frequency of apoptotic cells in the tumors. (F) Flow cytometric profiles of the tumor-infiltrating CD3+CD8+ T cells. (G) Ratio of granzyme B+ to tumor-infiltrating CD3+CD8+ T cells. (H) Frequency of apoptotic cells in the tumors. (I) Quantification of antigen-specific CTLs in spleens from the tumor-bearing mice. Ten mice from each group were used for in vivo experiments. Results shown in the graphs represent 3 independent experiments performed in triplicate. (D–I) Data represent the mean ± SD. ***P < 0.001, by 1-way ANOVA.