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.
View: Text | PDF
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

×

Figure 1

NANOG is inversely associated with the antitumor immune state of the TME in patients with cancer.

Options: View larger image (or click on image) Download as PowerPoint
NANOG is inversely associated with the antitumor immune state of the TME...
(A) Expression of the top 600 differentially expressed genes in patients with NANOGhi or NANOGlo melanoma. (B) GO term enrichment analysis for the top 5 biological processes controlled by differentially expressed genes among patients with high NANOG signature expression. (C and D) Comparisons of expression levels of T cell infiltration, antitumor response, and antitumor immune state signatures in NANOGlo (n = 315) and NANOGhi (n = 158) patients. (E) Kaplan-Meier analysis of overall survival (calculated as months to death or months to last follow-up) and median cutoffs values for NANOG signature expression levels (NANOGhi > median; NANOGlo < median, P = 0.0391). (F) Comparison of expression levels of antitumor immune state signatures in nonresponders with low levels (low, n = 8) or high levels (high, n = 9) of NANOG signature expression. The 25th and 75th percentiles were used as cutoff thresholds. (G) Pearson’s correlation between NANOG signature expression levels and antitumor immune states in nonresponders. (H) Correlation plot of NANOG and antitumor immune state signatures in pan-tumor types. Correlation and 2-tailed P values were assessed using the Pearson’s correlation coefficient and the unpaired Student’s t test. In the box plots, the top and bottom edges of boxes indicate the first and third quartiles, respectively; the center lines indicate the medians; and the ends of the whiskers indicate the maximum and minimum values, respectively. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test (C, D, and F). sig., signature.