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 3

NANOG repression enhances the response to anti–PD-1 therapy by inducing the immune-stimulatory feature in the TME.

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NANOG repression enhances the response to anti–PD-1 therapy by inducing ...
(A) Top: Quantification of NANOG expression in tumor cells at different stages of immune selection (P0–P3). Parallel stages without selection are labeled as N1–N3. Bottom: Representative Western blots. (B) Flow cytometric analysis of NANOG+ tumor cells and quantification of the frequency of NANOG+ tumor cells. (C–H) CT26 P3 tumor–bearing mice were administered siGFP or siNanog with or without anti–PD-1 antibody treatment. (C) Tumor growth curves and (D) changes in tumor volume 17 days after challenge compared with baseline. (E) Flow cytometric profiles of tumor-infiltrating CD3+CD8+ T cells. (F) Ratio of granzyme B+ to tumor-infiltrating CD3+CD8+ T cells. (G) Frequency of apoptotic cells in the tumors. (H) Quantification of antigen-specific CTLs in spleens from tumor-bearing mice. Ten mice from each group were used for in vivo experiments. Results in the graphs represent 3 independent experiments performed in triplicate. Data represent the mean ± SD. **P < 0.01 and ***P < 0.001, by 2-tailed Student’s t test (A and B) and 1-way ANOVA (E–H).