Immune checkpoint inhibitors (ICIs), exemplified by anti-PD-1 are promising treatments for many tumors. However, the majority of patients lack effective responses because of the emergence of immune-refractory tumors that disrupt the amplification of antitumor immunity. In many cases, one of the major causes of resistance to these agents is the limited tumor penetrance of effector T cells. Durable clinical responses using anti–PD-1 have been associated with T cell–inflamed tumor microenvironment (TME) favoring the infiltration of functional cytotoxic T lymphocytes (CTLs). Efforts to identify therapeutic approaches able to turn immune cold tumors hot by enhancing immune cell infiltration into the tumor bed are currently undertaken.
We analyzed transcriptomic data on patients with cancer treated with anti-PD-1and newly established preclinical mouse models refractory to anti-PD-1. The effect of genetic ablation or pharmacological inhibition of HDAC1 were approached by transwell T cell migration assay, Immunostaining, flow cytometry and RT-qPCR. We confirmed the enhanced therapeutic effect against tumors when combining anti-PD-1 with HDAC1 inhibitor in refractory tumor mouse models.
HDAC1 is a key factor for insufficient T cell infiltration and resistance to CTL-mediated killing in immune-refractory tumors. Ablation of HDAC1 significantly upregulates the expression of CXCL10 and MCL-1 in the refractory tumor cells, enforcing T cell infiltration and CTL-mediated apoptosis of the tumor cells. In immune-refractory tumor models, tumors were substantially smaller in size and tumor burden in the mice treated with both anti-PD-1 and HDAC1 inhibitor compared with those treated with either agent alone. The overall numbers of CD8 T cells and tumor-reactive CD8 T cells expressing granzyme B were significantly higher in the combination treatment group than in the other treatment groups.
Preliminary data suggest HDAC1 inhibition switched the immune phenotypes from an immune-refractory to an immune-stimulatory feature by simultaneously reversing NANOG-mediated immune-refractory states, thereby overcoming the resistance to PD-1 blockade.
The author.
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The author has declared no conflicts of interest.