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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.
Introduction
Immune checkpoint blockade (ICB) therapy elicits a marked clinical response in patients with various tumor types, changing the paradigm for cancer treatment (1-3). However, despite the developing field's potential to revolutionize cancer treatment, the emergence of immune-refractory tumors has limited its clinical success (4, 5). Among the diverse causes of the development of immunerefractory tumors, the cancer immunoediting theory has attracted attention, as it can explain the emergence of tumors refractory to antitumor immunity (6). Indeed, previous studies have provided evidence that cancer immunoediting triggered the adaptation of tumor cells to the host's immune system, thereby contributing to the generation of cancer cells with better survival advantages (7, 8). In this regard, we had found that immune selection by immunotherapy, such as vaccination or adoptive T cell transfer (ACT), drives the evolution of tumors toward immune-refractory states, such as resistance of tumor cells to T cell-mediated killing (9-12). Interestingly, the immune-refractory tumors were resistant to T cell-mediated killing and restricted host antitumor immunity (13). Thus, understanding the molecular mechanism that disrupts antitumor immunity could reveal potential targets for overcoming clinical limitations to ICB therapy.
Theoretically, the immune system should be capable of eradicating...