When the tumor volume reached an average of 100?mm3, the mice were given a vehicle either alone or in combination with SD70 and/or anti-CXCL10. flow cytometry. An in vivo subcutaneous transplanted tumor model and in vitro conditioned culture model were constructed to detect the quantitative and functional changes in CD8+ T cells. RNA sequencing and chromatin immunoprecipitation-PCR assays were used to explore the downstream regulatory mechanism of KDM4C in antitumor immunity. A C57BL/6?mouse tumor model was developed to evaluate the efficacy and safety of a triple therapy (the KDM4C-specific inhibitor SD70 plus RT and an anti-PD-L1 antibody) in lung cancer in vivo. Results Genetical or pharmacological inhibition of KDM4C specifically increased CD8+ T cell infiltration; promoted the proliferation, migration and activation of CD8+ T cells; and alleviated CD8+ T cell exhaustion in mouse tumor tissues. Mechanistically, KDM4C inhibition increased the binding of H3K36me3 to the CXCL10 promoter region, thus inducing CXCL10 transcription and enhancing the CD8+ T cell mediated antitumor immune response. More importantly, among the tested regimens, the triple therapy achieved the best therapeutic efficacy with tolerable toxicity in lung cancer. Conclusions Our data reveal a crucial role for KDM4C in antitumor immunity in lung cancer and indicate that targeting KDM4C in combination with radioimmunotherapy might be a promising synergistic strategy in lung cancer. strong class=”kwd-title” Keywords: radioimmunotherapy, lung neoplasms, tumor microenvironment Introduction The use of immune checkpoint inhibitors has become a powerful treatment strategy in many types of cancer. Immunotherapy is based on activating the immune system against tumor cells and is characterized by its fine specificity and ability to induce immune memory, which can achieve rapid and lasting tumor clearance.1 Despite the achievement of remarkable clinical success in several human tumors, the overall sensitivity of patients to immune checkpoint blockade (ICB) is relatively low.1 2 The average response rate of ICBs as a (R)-Oxiracetam monotherapy in patients with different tumor types is less than 30%.3 4 Therefore, improving the antitumor efficacy of ICB has become one of the main challenges in clinical application. There is a growing body of evidence showing that the efficacy of ICB is dependent on a strong antitumor immune response, which is usually impaired in most tumors.3 5 According to the immune cell type, tumors can be roughly divided into hot (T cell inflammation) or cold (T cells absent) tumors. Immunologically hot tumors are characterized by the presence of a large number of infiltrating CD8+ cytotoxic T cells (CTLs) and antigen-presenting cells (such as dendritic cells (DCs)), and rapid and sustained tumor clearance can often be achieved when tumors with this type of profile are treated with ICBs. In contrast, immunologically cold tumors are characterized by a lack of preexisting tumor-infiltrating lymphocytes (R)-Oxiracetam (TILs), and these tumors can be further subdivided into immune-excluded tumors, (R)-Oxiracetam in which T cells are attracted to the tumor but fail to infiltrate, and immune-desert tumors, in which T cell tumor infiltration is absent. Although ICBs aim to boost the bodys immune responses against Rabbit polyclonal to HER2.This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases.This protein has no ligand binding domain of its own and therefore cannot bind growth factors.However, it does bind tightly to other ligand-boun tumors, immunotherapy in patients without preexisting TILs is rarely effective.6C8 Numerous studies have shown that CD8+ T cells are the primary mediators of antitumor immunity. Thus, enhancing their infiltration into tumors has always been at the center of immunotherapeutic strategies.9 10 Additionally, radiotherapy (RT) has been proven to enhance antitumor immunity by releasing tumor-associated antigens and promoting TIL infiltration into tumors.11 12 However, the synergistic effects achieved with RT combined with immunotherapy are still clinically unsatisfactory. Epigenetics is defined as the dynamic modification of the genome without changing the DNA sequence. Abnormal epigenetic changes usually lead to (R)-Oxiracetam aberrant gene expression and tumor promotion.13 14 At present, epigenetic (R)-Oxiracetam therapy has been shown to modulate various components of the tumor microenvironment (TME), including increasing tumor-associated antigen expression, enhancing antigen processing and presentation, inducing CD8+ T cell infiltration and activation, preventing or reversing T cell exhaustion, and enhancing the abundance of infiltrating effector T cells and/or memory T cells.15 16 Therefore, the combination of epigenetic therapy and immunotherapy is considered a promising treatment strategy for cancer.15 16 Histone lysine-specific demethylase 4C (KDM4C) can specifically catalyze the demethylation of.