STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance.

Acute myeloid leukemia (AML) is a heterogenous disease characterized by the clonal expansion of myeloid progenitor cells. Despite recent advancements in the treatment of AML, relapse still remains a significant challenge, necessitating the development of innovative therapies to eliminate minimal residual disease. One promising approach to address these unmet clinical needs is natural killer (NK) cell immunotherapy. To implement such treatments effectively, it is vital to comprehend how AML cells escape the NK-cell surveillance. Signal transducer and activator of transcription 3 (STAT3), a component of the Janus kinase (JAK)-STAT signaling pathway, is well-known for its role in driving immune evasion in various cancer types. Nevertheless, the specific function of STAT3 in AML cell escape from NK cells has not been deeply investigated. In this study, we unravel a novel role of STAT3 in sensitizing AML cells to NK-cell surveillance. We demonstrate that STAT3-deficient AML cell lines are inefficiently eliminated by NK cells. Mechanistically, AML cells lacking STAT3 fail to form an immune synapse as efficiently as their wild-type counterparts due to significantly reduced surface expression of intercellular adhesion molecule 1 (ICAM-1). The impaired killing of STAT3-deficient cells can be rescued by ICAM-1 overexpression proving its central role in the observed phenotype. Importantly, analysis of our AML patient cohort revealed a positive correlation between ICAM1 and STAT3 expression suggesting a predominant role of STAT3 in ICAM-1 regulation in this disease. In line, high ICAM1 expression correlates with better survival of AML patients underscoring the translational relevance of our findings. Taken together, our data unveil a novel role of STAT3 in preventing AML cells from escaping NK-cell surveillance and highlight the STAT3/ICAM-1 axis as a potential biomarker for NK-cell therapies in AML.

In-depth analysis of the interplay between oncogenic mutations and NK cell-mediated cancer surveillance in solid tumors.

Natural killer (NK) cells play a crucial role in antitumoral and antiviral responses. Yet, cancer cells can alter themselves or the microenvironment through the secretion of cytokines or other factors, hindering NK cell activation and promoting a less cytotoxic phenotype. These resistance mechanisms, often referred to as the "hallmarks of cancer" are significantly influenced by the activation of oncogenes, impacting most, if not all, of the described hallmarks. Along with oncogenes, other types of genes, the tumor suppressor genes are frequently mutated or modified during cancer. Traditionally, these genes have been associated with uncontrollable tumor growth and apoptosis resistance. Recent evidence suggests oncogenic mutations extend beyond modulating cell death/proliferation programs, influencing cancer immunosurveillance. While T cells have been more studied, the results obtained highlight NK cells as emerging key protagonists for enhancing tumor cell elimination by modulating oncogenic activity. A few recent studies highlight the crucial role of oncogenic mutations in NK cell-mediated cancer recognition, impacting angiogenesis, stress ligands, and signaling balance within the tumor microenvironment. This review will critically examine recent discoveries correlating oncogenic mutations to NK cell-mediated cancer immunosurveillance, a relatively underexplored area, particularly in the era dominated by immune checkpoint inhibitors and CAR-T cells. Building on these insights, we will explore opportunities to improve NK cell-based immunotherapies, which are increasingly recognized as promising alternatives for treating low-antigenic tumors, offering significant advantages in terms of safety and manufacturing suitability.

Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia.

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen-presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen-presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen-presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA-B alleles had a higher HPV antigen-presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2-3) than in cervicitis or early-stage CIN (CIN1): around half of CIN2-3 had LOH of any HLA class I. Moreover, the antigen-presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA-B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long-term infection and progression to advanced lesions.

The Multifaceted Role of Tissue-Resident Memory T Cells.

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.

Qizhu anticancer prescription enhances immunosurveillance of liver cancer cells by regulating p21-dependent secretory phenotypes.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, largely due to the limitations of available therapeutic strategies. The traditional Chinese medicine Qizhu Anticancer Prescription (QZACP) can improve the quality of life and prolong the survival time of patients with HCC. However, the precise mechanisms underlying the anti-cancer properties of QZACP remain unclear. PURPOSE: This study examined the anti-hepatocarcinogenic properties of QZACP, with a specific focus on its influence on the p21-activated secretory phenotype (PASP)-mediated immune surveillance, to elucidate the underlying molecular pathways involved in HCC. MATERIALS AND METHODS: Cell proliferation was measured using the Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, and clonogenic assays. The cell cycle was evaluated using flow cytometry, and senescence was identified by staining with senescence-associated beta-galactosidase (SA-ß-gal). A primary liver cancer model produced by diethylnitrosamine was established in C57 BL/6 mice to assess the tumor-inhibitory effect of QZACP. The liver's pathological characteristics were examined using hematoxylin and eosin staining. PASP screening was performed using GeneCards, DisGeNet, Online Mendelian Inheritance in Man, and The Cancer Genome Atlas databases. Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and Transwell migration assays were performed. RESULTS: Serum containing QZACP enhanced p21 expression, triggered cell cycle arrest, accelerated cell senescence, and suppressed cell proliferation in Huh7 and MHCC-97H liver cancer cells. QZACP reduced the quantity and dimensions of liver tumor nodules and enhanced p21 protein expression, SA-ß-Gal staining in tumor lesions, and cytotoxic CD8+ T cell infiltration. Bioinformatic analyses indicated that PASP factors, including hepatocyte growth factor, decorin (DCN), dermatopontin, C-X-C motif chemokine ligand 14 (CXCL14), and Wnt family member 2 (WNT2), play an important role in the development of HCC. In addition, these factors are associated with the presence of natural killer cells and CD8+ T cells within tumors. Western blotting and ELISA confirmed that QZACP increased DCN, CXCL14, and WNT2 levels in tumor tissues and peripheral blood. CONCLUSIONS: QZACP's suppression of HCC progression may involve cell senescence mediated via p21 upregulation, DCN, CXCL14, and WNT2 secretion, and reversal of the immunosuppressive microenvironment. This study provides insights that can be used in the development of new treatment strategies for HCC.

NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance.

The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

Sonocatalytic oncolysis microbiota curb intrinsic microbiota lactate metabolism and blockade CD24-Siglec10 immune escape to revitalize immunological surveillance.

Intrinsic lactate retention of chemically- or genetically-engineered bacteria therapy aggravates tumor immunosuppression, which will collaborate with immune escape to cause immunological surveillance failure. To address them, sonocatalytic oncolysis Escherichia coli (E.coli) that chemically chelated anti-CD24 and TiO1+x have been engineered to blockade CD24-siglec10 interaction, regulate microbiota colonization and curb its lactate metabolism, which are leveraged to revitalize immunological surveillance and repress breast cancer. The chemically-engineered E.coli inherited their parent genetic information and expansion function. Therefore, their intrinsic hypoxia tropism and CD24 targeting allow them to specifically accumulate and colonize in solid breast cancer to lyse tumor cells. The conjugated CD24 antibody is allowed to blockade CD24-Siglec10 signaling axis and revitalize immunological surveillance. More significantly, the chelated TiO1+x sonosensitizers produce ROS to render bacteria expansion controllable and curb immunosuppression-associated lactate birth that are usually neglected. Systematic experiments successfully vlaidate hypoxia-objective active targeting, sonocatalytic therapy, microbiota expansion-enabled oncolysis, CD24-Siglec10 communication blockade and precise microbiota abundance & lactate metabolism attenuations. These actions contribute to the potentiated anti-tumor immunity and activated anti-metastasis immune memory against breast cancer development. Our pioneering work provide a route to sonocatalytic cancer immunotherapy.

Germline variants alter immune surveillance.

Germline-derived epitopes shape tumor development through immunoediting.

circATAD2 mitigates CD8+ T cells antitumor immune surveillance in breast cancer via IGF2BP3/m6A/PD-L1 manner.

Immune surveillance and chemotherapy sensitivity play critical functions in the tumorigenesis of breast cancer (BC). Emerging findings have indicated that circular RNA (circRNA) and N6-methyladenosine (m6A) both participate in the BC tumorigenesis. Here, present study aimed to investigate the roles of m6A-modified circATAD2 on BC and explore better understanding for BC precision therapeutic. Results reported that m6A-modifid circRNA (m6A-circRNA) microarray revealed the m6A-circRNA landscape in BC. M6A-modifid circATAD2 upregulated in BC samples and was closely correlated to poor prognosis. Functionally, circATAD2 promoted the immune evasion of BC cells and reduced the CD8+ T cells' killing effect. Mechanistically, MeRIP-seq unveiled the m6A modification in the 3'-UTR of PD-L1 mRNA, which was bound by circATAD2 and recognized by m6A reader IGF2BP3 to enhance PD-L1 mRNA stability and expression. In summary, these findings revealed the circATAD2/m6A/IGF2BP3/PD-L1 axis in BC immune surveillance, suggesting the potential that circATAD2 as a potential target for PD-L1-mediated BC.

Predictability of B cell clonal persistence and immunosurveillance in breast cancer.

B cells and T cells are important components of the adaptive immune system and mediate anticancer immunity. The T cell landscape in cancer is well characterized, but the contribution of B cells to anticancer immunosurveillance is less well explored. Here we show an integrative analysis of the B cell and T cell receptor repertoire from individuals with metastatic breast cancer and individuals with early breast cancer during neoadjuvant therapy. Using immune receptor, RNA and whole-exome sequencing, we show that both B cell and T cell responses seem to coevolve with the metastatic cancer genomes and mirror tumor mutational and neoantigen architecture. B cell clones associated with metastatic immunosurveillance and temporal persistence were more expanded and distinct from site-specific clones. B cell clonal immunosurveillance and temporal persistence are predictable from the clonal structure, with higher-centrality B cell antigen receptors more likely to be detected across multiple metastases or across time. This predictability was generalizable across other immune-mediated disorders. This work lays a foundation for prioritizing antibody sequences for therapeutic targeting in cancer.

T Cell Surveillance during Cutaneous Viral Infections.

The skin is a complex tissue that provides a strong physical barrier against invading pathogens. Despite this, many viruses can access the skin and successfully replicate in either the epidermal keratinocytes or dermal immune cells. In this review, we provide an overview of the antiviral T cell biology responding to cutaneous viral infections and how these responses differ depending on the cellular targets of infection. Much of our mechanistic understanding of T cell surveillance of cutaneous infection has been gained from murine models of poxvirus and herpesvirus infection. However, we also discuss other viral infections, including flaviviruses and papillomaviruses, in which the cutaneous T cell response has been less extensively studied. In addition to the mechanisms of successful T cell control of cutaneous viral infection, we highlight knowledge gaps and future directions with possible impact on human health.

IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer.

BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.

Lymphatic vessels in the age of cancer immunotherapy.

Lymphatic transport maintains homeostatic health and is necessary for immune surveillance, and yet lymphatic growth is often associated with solid tumour development and dissemination. Although tumour-associated lymphatic remodelling and growth were initially presumed to simply expand a passive route for regional metastasis, emerging research puts lymphatic vessels and their active transport at the interface of metastasis, tumour-associated inflammation and systemic immune surveillance. Here, we discuss active mechanisms through which lymphatic vessels shape their transport function to influence peripheral tissue immunity and the current understanding of how tumour-associated lymphatic vessels may both augment and disrupt antitumour immune surveillance. We end by looking forward to emerging areas of interest in the field of cancer immunotherapy in which lymphatic vessels and their transport function are likely key players: the formation of tertiary lymphoid structures, immune surveillance in the central nervous system, the microbiome, obesity and ageing. The lessons learnt support a working framework that defines the lymphatic system as a key determinant of both local and systemic inflammatory networks and thereby a crucial player in the response to cancer immunotherapy.

Urolithin-A Promotes CD8+ T Cell-mediated Cancer Immunosurveillance via FOXO1 Activation.

Naïve T cells are key players in cancer immunosurveillance, even though their function declines during tumor progression. Thus, interventions capable of sustaining the quality and function of naïve T cells are needed to improve cancer immunoprevention.In this context, we studied the capacity of Urolithin-A (UroA), a potent mitophagy inducer, to enhance T cell-mediated cancer immunosurveillance.We discovered that UroA improved the cancer immune response by activating the transcription factor FOXO1 in CD8+ T cell. Sustained FOXO1 activation promoted the expression of the adhesion molecule L-selectin (CD62L) resulting in the expansion of the naïve T cells population. We found that UroA reduces FOXO1 phosphorylation favoring its nuclear localization and transcriptional activity. Overall, our findings determine FOXO1 as a novel molecular target of UroA in CD8+ T cells and indicate UroA as promising immunomodulator to improve cancer immunosurveillance. SIGNIFICANCE: Urolithin-A, a potent mitophagy inducer, emerges as a promising tool to enhance cancer immunosurveillance by activating the FOXO1 transcription factor in CD8+ T cells. This activation promotes the expansion of naïve T cells, offering a novel avenue for improving cancer immune response and highlighting UroA as a potential immunomodulator for bolstering our body's defenses against cancer.

Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells.

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

Chronic SIV-Induced neuroinflammation disrupts CCR7+ CD4+ T cell immunosurveillance in the rhesus macaque brain.

CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.

Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory.

Metastasis arises from disseminated tumour cells (DTCs) that are characterized by intrinsic phenotypic plasticity and the capability of seeding to secondary organs. DTCs can remain latent for years before giving rise to symptomatic overt metastasis. In this context, DTCs fluctuate between a quiescent and proliferative state in response to systemic and microenvironmental signals including immune-mediated surveillance. Despite its relevance, how intrinsic mechanisms sustain DTCs plasticity has not been addressed. By interrogating the epigenetic state of metastatic cells, we find that tumour progression is coupled with the activation of oncogenic enhancers that are organized in variable interconnected chromatin domains. This spatial chromatin context leads to the activation of a robust transcriptional response upon repeated exposure to retinoic acid (RA). We show that this adaptive mechanism sustains the quiescence of DTCs through the activation of the master regulator SOX9. Finally, we determine that RA-stimulated transcriptional memory increases the fitness of metastatic cells by supporting the escape of quiescent DTCs from NK-mediated immune surveillance. Overall, these findings highlight the contribution of oncogenic enhancers in establishing transcriptional memories as an adaptive mechanism to reinforce cancer dormancy and immune escape, thus amenable for therapeutic intervention.

Epithelial recognition and elimination against aberrant cells.

Epithelial cells, which are non-immune cells, not only function as a physical defence barrier but also continuously monitor and eliminate aberrant epithelial cells in their vicinity. In other words, it has become evident that epithelial cells possess immune cell-like functions. In fact, recent research has revealed that epithelial cells recognise the Major Histocompatibility Complex I (MHC-I) of aberrant cells as a mechanism for surveillance. This cellular defence mechanism of epithelial cells probably detects aberrant cells more promptly than the conventional immune response, making it a novel and primary biological defence. Furthermore, there is the potential for this new immune-like biological defence mechanism to establish innovative treatment for disease prevention, leading to increasing anticipation for its future medical applications. In this review, we aim to summarise the recognition and attack mechanisms of aberrant cells by epithelial cells in mammals, with a particular focus on the field of cancer. Additionally, we discuss the potential therapeutic applications of epithelial cell-based defence against cancer, including novel prophylactic treatment methods based on molecular mechanisms.

Establishing evidence for immune surveillance of ß-cell senescence.

Cellular senescence is a programmed state of cell cycle arrest that involves a complex immunogenic secretome, eliciting immune surveillance and senescent cell clearance. Recent work has shown that a subpopulation of pancreatic ß-cells becomes senescent in the context of diabetes; however, it is not known whether these cells are normally subject to immune surveillance. In this opinion article, we advance the hypothesis that immune surveillance of ß-cells undergoing a senescence stress response normally limits their accumulation during aging and that the breakdown of these mechanisms is a driver of senescent ß-cell accumulation in diabetes. Elucidation and therapeutic activation of immune surveillance mechanisms in the pancreas holds promise for the improvement of approaches to target stressed senescent ß-cells in the treatment of diabetes.