Abstract Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to cross-present tumor cell-associated antigens to naïve T cells, DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor growth and tumor cell dissemination. Within an immunosuppressive tumor microenvironment, DC antitumor functions can, however, be severely impaired. In this review, we focus on the mechanisms of DC capture and activation by tumor cell antigens and the role of the tumor microenvironment in shaping DC functions, taking advantage of recent studies showing the phenotype acquisition, transcriptional state and functional programs revealed by scRNA-seq analysis. The therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is also discussed. 

https://www.nature.com/articles/s41423-023-00990-6.pdf

Dendritic cell subsets in cancer immunity and tumor antigen sensing

p63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon-Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G(2)/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and DeltaNp63alpha are associated in vivo and a conserved alpha-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. DeltaNp63alpha, but not the AEC mutants repress CCAAT-dependent transcription of G(2)/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G(2)/M promoters, while normally present on 14-3-3sigma, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G(2)/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations.

Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63

Maintenance of genome integrity is a dynamic process involving complex regulation systems. Defects in one or more of these pathways could result in cancer. The most important tumor-suppressor is the transcription factor p53, and its functional inactivation is frequently observed in many tumor types. The tumor suppressive function of p53 is mainly attributed to its ability to regulate numerous target genes at the transcriptional level. While the mechanism of transcriptional induction by p53 is well characterized, p53-dependent repression is not understood in detail. Here, we review the manifold mechanisms of p53 as a transcriptional repressor. We classify two different categories of repressed genes based on the underlying mechanism, and novel mechanisms which involve regulation through noncoding RNAs are discussed. The complete elucidation of p53 functions is important for our understanding of its tumor-suppressor activity and, therefore, represents the key for the development of novel therapeutic approaches.

/pdf/one-function-multiple-mechanisms-the-manifold-activities-of-49pabr57xu.pdf

One Function—Multiple Mechanisms: The Manifold Activities of p53 as a Transcriptional Repressor

Following DNA-damage, the tumor suppressor p53 activates G1/S blocking and apoptotic genes, and represses other genes, including those involved in G2/M transition. In this latter system, it acts through the CCAAT-binding histone-like NF-Y. Several groups have reported that p53 is associated to promoters in unstressed conditions. We developed an oligo-based array containing 179 human promoters, enriched in genes involved in the DNA-damage and ER-stress response. We performed ChIP on chip experiments with p53 and NF-Y in cells under normal growing conditions. We identified 46 new p53 targets and noted (i) a significant enrichment in genes of the ER-stress response, including crucial regulators such as XBP1 and C/EBPbeta (ii) genes whose products are involved in the regulation of p53 function. Several genes were validated by conventional ChIP. DNA-damage dependent PCAF-mediated acetylation was observed on most, but not all promoters. The effect of p53 activation was checked by RT-PCR and transfections in HCT116 wt, E6 and p53-/- cells: most promoters were actively repressed upon Adriamycin treatment or following p53 transfection in p53-/- cells. In particular, the behaviour of some of the genes (BRCA1, RAD23 and RAD17) is consistent with a feedback loop regulation on p53 levels. Finally, there is a large overlap (66%) between p53 and NF-Y targets. Our data reinstate the physiological importance of p53 promoter recognition and direct transcriptional repression as a mechanism to cope with DNA-damage.

Repression of new p53 targets revealed by ChIP on chip experiments.

C-1305 [S-[[3-(dimethylamino)propyl]amino]-8-hydroxy-6H-v-triazolo[4,5,1-de]acridin-6-one] is a triazoloacridone with excellent activity in colon cancer models. The mechanism of C-1305 is unknown, although similarities in the chemical structure between C-1305 and amsacrine suggest common cellular targets. Here, we report that C-1305 is a topoisomerase II poison that is able to induce cleavable complexes with topoisomerase II in vitro as well as in living cells. Even at optimal concentrations, C-1305 is a much weaker inducer of cleavable complexes than amsacrine. Because the cytotoxic activities of the two compounds after continuous drug exposure are comparable, these findings suggest that the low levels of cleavable complexes induced by C-1305 may be unusually toxic. In contrast to amsacrine, the cytotoxicity of C-1305 is strongly time-dependent, with at least 24 h of drug exposure required for optimal cytotoxicity. The p53 tumor suppressor is inactivated in the majority of human tumors, including colorectal cancers. We therefore compared the long-term cytotoxic effects of C-1305, amsacrine, and doxorubicin on human cell lines in which the p53 or p21 pathways have been specifically disrupted by targeted homologous recombination. Disruption of p53 and p21 had minor influence on the cytotoxicity of doxorubicin, whereas p53 but not p21 disruption was associated with increased resistance to amsacrine. In marked contrast, disruption of p53 and p21 was associated with increased sensitivity to C-1305. Taken together, our results show that exposure to C-1305 is accompanied by the formation of low levels of potent cleavable complexes that are selectively toxic toward tumor cells with defective p53 function.

The antitumor triazoloacridone C-1305 is a topoisomerase II poison with unusual properties.

Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers.

The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive.The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression.We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration.Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers. 

/pdf/rorgt-agonist-enhances-anti-pd-1-therapy-by-promoting-2gpu8f7w.pdf

RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers

Expression of the human DNA topoisomerase II (topo II) gene is positively regulated by the binding of the nuclear factor Y (NF-Y) transcription factor to four of five inverted CCAAT boxes (ICBs) located in its promoter. We have demonstrated previously that expression of the p53 tumor suppressor inhibits human topo II promoter activity in murine (10)1 cells. In this report, we demonstrate that the inhibition of topo II gene expression by wild-type p53 correlates with the decreased binding of the transcription factor NF-Y to the first four ICBs of the topo II promoter. The expression of mutant p53 does not affect the binding of NF-Y. In NIH3T3 cells, we show that topo II-targeted drugs inhibit the binding of NF-Y to ICB sites in the topo II promoter. This effect is seen not only with drugs that result in DNA strand breaks but also with drugs that inhibit the catalytic activity of topo II, and even with the mitotic spindle inhibitor, vinblastine. Further experiments with p53-null (10)1 cells treated with these same drugs also demonstrate decreased NF-Y binding to the topo II ICBs. The data presented points to the existence of both p53-dependent and -independent mechanisms for regulating NF-Y binding to ICBs in the topo II promoter and thus the modulation of topo II gene expression. The efficient transcription and replication of DNA requires changes in its double-strand topology at specific times during the cell cycle. These topological alterations are carried out by the ubiquitously expressed, homodimeric nuclear protein, topoisomerase II (topo II). Topo II can relieve supercoiling that results during DNA replication and is an essential enzyme for decatenation of sister chromatids at mitosis. The action of topo II involves the cleavage of one DNA double strand, the passage of a transfer double strand through the break, and religation of the cleaved DNA. During the decat

Nuclear factor-Y binding to the topoisomerase IIα promoter is inhibited by both the p53 tumor suppressor and anticancer drugs

Natural killer (NK) cells and T cells play crucial roles in liver metastatic cancer, particularly through their cytotoxic effects on tumor cells. Although existing evidence suggests a functional network of mutual regulation between NK and T cells, the nature of their interaction and its role in liver metastasis remain elusive. In this study, we analyzed single-cell transcriptomics of liver metastases and adjacent tissues from nasopharyngeal carcinoma (NPC), thyroid carcinoma (THCA), breast cancer (BC), colorectal cancer (CRC) and cervical cancer (CESC) to uncover the NK-T cell interaction network and its functional implications. In adjacent tissues, we observed increased infiltration of CD8+ NKT-like cells, γδT cells, and NK cells. The interaction between CD8+ NKT-like cells, CD8+ T cells, γδT cells, and NK cells were enhanced, with stronger signals associated with T and NK cell functions. Notably, CD8+ NKT-like cells, CD8+ T cells, and γδT cells exhibited an increased capacity to activate NK cells. These T cell subsets promoted NK cell anti-tumor activity via CD48-CD244 and TNF-TNFR signaling pathways, which in turn activated the ERK, JNK, and MAPK cascades. Our findings provide valuable insights into the NK-T cell interaction network in liver metastatic cancer, highlighting its potential as a therapeutic target.

Single-cell transcriptomics analysis reveals a disrupted NK-T cell interaction network in liver metastatic cancer

Phase 1 clinical trial of EpCAM CAR-T cell therapy in patients with gastrointestinal cancers.

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