Rewiring the T cell-suppressive cytokine landscape of the tumor microenvironment: a new frontier for precision anti-cancer therapy.

T lymphocytes that infiltrate the tumor microenvironment (TME) often fail to function as effective anti-cancer agents. Within the TME, cell-to-cell inhibitory interactions play significant roles in dampening their anti-tumor activities. Recent studies have revealed that soluble factors released in the TME by immune and non-immune cells, as well as by tumor cells themselves, contribute to the exacerbation of T cell exhaustion. Our understanding of the cytokine landscape of the TME, their interrelationships, and their impact on cancer development is still at its early stages. In this review, we aim to shed light on Interleukin (IL) -6, IL-9, and IL-10, a small group of JAK/STAT signaling-dependent cytokines harboring T cell-suppressive effects in the TME and summarize their mechanisms of action. Additionally, we will explore how advancements in scientific research can help us overcoming the obstacles posed by cytokines that suppress T cells in tumors, with the ultimate objective of stimulating further investigations for the development of novel therapeutic strategies to counteract their tumor-promoting activities.

Formaldehyde promotes tumor-associated macrophage polarizations and functions through induction of HIF-1α-mediated glycolysis.

Formaldehyde (FA) exposure has been positively correlated with many diseases including various types of cancers. However, the mechanisms of FA-related carcinogenesis are still unclear. Tumor-associated macrophages (TAMs) are the most abundant immune cells in tumor microenvironment, which is a heterogeneous population consist of both pro-inflammatory (M1) and immunosuppressive (M2) cells. TAMs are deeply involved in tumor development and progression. Our previous studies demonstrated that FA enhanced M1 polarization of macrophages through induction of HIF-1α-mediated glycolysis. To examine if TAM polarizations are also potentiated by FA, BALB/c nude mice were inoculated with A549 cells to develop subcutaneous tumors and exposed to 2.0 mg/m3 FA for 14 days. Significant increases of both M1 and M2 polarizations of TAMs were observed in tumor tissues of FA-exposed mice. After confirmation of the potentiation effects in RAW264.7 and THP-1-derived in vitro TAM models, FA at 25 and 50 µM was found to enhance TAM immunosuppressive functions and glycolytic metabolism. In addition, FA-induced glycolysis in TAMs was reversed by a specific HIF-1α inhibitor PX-478 at 5 µM, and suppression of glycolytic metabolism with a glucose analog 2-DG at 1 mM also alleviated FA-potentiated TAM functions, which indicated that FA induced TAM polarizations through the upregulation of HIF-1α-mediated glycolysis. These results illustrated a potential carcinogenic mechanism of FA through metabolic disturbance of tumor immunity, which could be utilized to develop preventative or therapeutic agents for FA-induced carcinogenesis and immune disorders.

Concurrent infections of cells by two pathogens can enable a reactivation of the first pathogen and the second pathogen's accelerated T-cell exhaustion.

When multiple intracellular pathogens, such as viruses, bacteria, fungi and protozoan parasites, infect the same host cell, they can help each other. A pathogen can substantially help another pathogen by disabling cellular immune defenses, using non-coding ribonucleic acids and/or pathogen proteins that target interferon-stimulated genes and other genes that express immune defense proteins. This can enable reactivation of a latent first pathogen and accelerate T-cell exhaustion and/or T-cell suppression regarding a second pathogen. In a worst-case scenario, accelerated T-cell exhaustion and/or T-cell suppression regarding the second pathogen can impair T-cell functionality and allow a first-time, immunologically novel second pathogen infection to escape all adaptive immune system defenses, including antibodies. The interactions of herpesviruses with concurrent intracellular pathogens in epithelial cells and B-cells, the interactions of the human immunodeficiency virus with Mycobacterium tuberculosis in macrophages and the interactions of Toxoplasma gondii with other pathogens in almost any type of animal cell are considered. The reactivation of latent pathogens and the acceleration of T-cell exhaustion for the second pathogen can explain several puzzling aspects of viral epidemics, such as COVID-19 and their unusual comorbidity mortality rates and post-infection symptoms.

TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown. METHODS: To interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients. RESULTS: We demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT, LAG3, and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse. CONCLUSIONS: Our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.

[Kaposi sarcoma-a complication of treatment refractory ulcerative colitis]. / Das Kaposi-Sarkom ­ eine Komplikation bei therapierefraktärer Colitis ulcerosa.

We report on the incidental finding of Kaposi sarcoma of the colon in the setting of refractory ulcerative colitis treatment. The patient was under long-term immunosuppression with infliximab, vedolizumab, and prednisolone. Serologic analysis excluded human immunodeficiency virus (HIV) infection.

HLA-A2 Promotes the Therapeutic Effect of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Hyperoxic Lung Injury.

Mesenchymal stem cells (MSCs) are one of the most extensively studied stem cell types owing to their capacity for differentiation into multiple lineages as well as their ability to secrete regenerative factors and modulate immune functions. However, issues remain regarding their further application for cell therapy. Here, to demonstrate the superiority of the improvement of MSCs, we divided umbilical cord blood-derived MSCs (UCB-MSCs) from 15 donors into two groups based on efficacy and revealed donor-dependent variations in the anti-inflammatory effect of MSCs on macrophages as well as their immunoregulatory effect on T cells. Through surface marker analyses (242 antibodies), we found that HLA-A2 was positively related to the anti-inflammatory and immunoregulatory function of MSCs. Additionally, HLA-A2 mRNA silencing in MSCs attenuated their therapeutic effects in vitro; namely, the suppression of LPS-stimulated macrophages and phytohemagglutinin-stimulated T cells. Moreover, HLA-A2 silencing in MSCs significantly decreased their therapeutic effects in a rat model of hyperoxic lung damage. The present study provides novel insights into the quality control of donor-derived MSCs for the treatment of inflammatory conditions and diseases.

Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia.

BACKGROUND & AIMS: The liver plays crucial roles in the regulation of immune defense during acute systemic infections. However, the roles of liver cellular clusters and intercellular communication in the progression of endotoxemia have not been well-characterized. METHODS: Single-cell RNA sequencing analysis was performed, and the transcriptomes of 19,795 single liver cells from healthy and endotoxic mice were profiled. The spatial and temporal changes in hepatocytes and non-parenchymal cell types were validated by multiplex immunofluorescence staining, bulk transcriptomic sequencing, or flow cytometry. Furthermore, we used an adeno-associated virus delivery system to confirm the major mechanisms mediating myeloid cell infiltration and T-cell suppression in septic murine liver. RESULTS: We identified a proinflammatory hepatocyte (PIH) subpopulation that developed primarily from periportal hepatocytes and to a lesser extent from pericentral hepatocytes and played key immunoregulatory roles in endotoxemia. Multicellular cluster modeling of ligand-receptor interactions revealed that PIHs play a crucial role in the recruitment of macrophages via the CCL2-CCR2 interaction. Recruited macrophages (RMs) released cytokines (e.g., IL6, TNFα, and IL17) to induce the expression of inhibitory ligands, such as PD-L1, on hepatocytes. Subsequently, RM-stimulated hepatocytes led to the suppression of CD4+ and memory T-cell subsets partly via the PD-1/PD-L1 interaction in endotoxemia. Furthermore, sinusoidal endothelial cells expressed the highest levels of proapoptotic and inflammatory genes around the periportal zone. This pattern of gene expression facilitated increases in the number of fenestrations and infiltration of immune cells in the periportal zone. CONCLUSIONS: Our study elucidates unanticipated aspects of the cellular and molecular effects of endotoxemia on liver cells at the single-cell level and provides a conceptual framework for the development of novel therapeutic approaches for acute infection. LAY SUMMARY: The liver plays a crucial role in the regulation of immune defense during acute systemic infections. We identified a proinflammatory hepatocyte subpopulation and demonstrated that the interactions of this subpopulation with recruited macrophages are pivotal in the immune response during endotoxemia. These novel findings provide a conceptual framework for the discovery of rational therapeutic targets in acute infection.

Identification of a CD4+ T cell line with Treg-like activity.

Regulatory T cells (Tregs) suppress adaptive immunity and inflammation. Although they play a role in suppressing anti-tumor responses, development of therapeutics that target Tregs is limited by their low abundance, heterogeneity, and lack of specific cell surface markers. We isolated human PBMC-derived CD4+ CD25high Foxp3+ Tregs and demonstrate they suppress stimulated CD4+ PBMCs in a cell contact-dependent manner. Because it is not possible to functionally characterize cells after intracellular Foxp3 staining, we identified a human T cell line, MoT, as a model of human Foxp3+ Tregs. Unlike Jurkat T cells, MoT cells share common surface markers consistent with human PBMC-derived Tregs such as: CD4, CD25, GITR, LAG-3, PD-L1, CCR4. PBMC-derived Tregs and MoT cells, but not Jurkat cells, inhibited proliferation of human CD4+PBMCs in a ratio-dependent manner. Transwell membrane separation prevented suppression of stimulated CD4+PBMC proliferation by MoT cells and Tregs, suggesting cell-cell contact is required for suppressive activity. Blocking antibodies against PD-L1, LAG-3, GITR, CCR4, HLA-DR, or CTLA-4 did not reverse the suppressive activity.We show that human PBMC-derived Tregs and MoT cells suppress stimulated CD4+PBMCs in a cell contact-dependent manner, suggesting that a Foxp3+Treg population suppresses immune responses by an uncharacterized cell contact-dependent mechanism.

Antibodies Enhance the Suppressive Activity of Extracellular Vesicles in Mouse Delayed-Type Hypersensitivity.

Previously, we showed that mouse delayed-type hypersensitivity (DTH) can be antigen-specifically downregulated by suppressor T cell-derived miRNA-150 carried by extracellular vesicles (EVs) that target antigen-presenting macrophages. However, the exact mechanism of the suppressive action of miRNA-150-targeted macrophages on effector T cells remained unclear, and our current studies aimed to investigate it. By employing the DTH mouse model, we showed that effector T cells were inhibited by macrophage-released EVs in a miRNA-150-dependent manner. This effect was enhanced by the pre-incubation of EVs with antigen-specific antibodies. Their specific binding to MHC class II-expressing EVs was proved in flow cytometry and ELISA-based experiments. Furthermore, by the use of nanoparticle tracking analysis and transmission electron microscopy, we found that the incubation of macrophage-released EVs with antigen-specific antibodies resulted in EVs' aggregation, which significantly enhanced their suppressive activity in vivo. Nowadays, it is increasingly evident that EVs play an exceptional role in intercellular communication and selective cargo transfer, and thus are considered promising candidates for therapeutic usage. However, EVs appear to be less effective than their parental cells. In this context, our current studies provide evidence that antigen-specific antibodies can be easily used for increasing EVs' biological activity, which has great therapeutic potential.

VISTA Stimulation of VSIG4-Positive Macrophages Strongly Suppresses T Cell Proliferation via Excessive Nitric Oxide Production in Sepsis.

Organ damage and immune deficiency are important problems in sepsis caused by an excessive immune response. There is controversy about the cause of immune suppression. In this study, we investigated the roles of macrophages that exhibit excessive activity on T cell immunity. Peritoneal macrophages from mice with cecal ligation and puncture (CLP)-induced sepsis migrated to different organs. In particular, V-set immunoglobulin (Ig)-domain-containing 4 (VSIG4) positive macrophages appeared in the spleen 48 h after CLP induction. When cocultured with splenic T cells, VSIG4(+) cells inhibited the proliferation of activated T cells through the release of nitric oxide (NO) compared to VSIG4(-) cells. Stimulation of VSIG4(+) cells with V-domain Ig suppressor of T cell activation (VISTA) antibody increased the expression of several cytokine genes and the release of NO, but not phagocytosis, compared to those of hamster IgG-stimulated VSIG4(+) cells. When cocultured with splenic T cells, VISTA-stimulated VSIG4(+) cells induced excessive T cell suppression via more NO secretion compared to hamster IgG-stimulated VSIG4(+) cells. Taken together, the current study demonstrates that VSIG4(+) peritoneal macrophages play important roles in inducing immunosuppression and that VISTA acts as a costimulatory receptor in these cells. These data suggest that blocking the migration of VSIG4(+) cells might alleviate excessive immune activity and that blocking VISTA on VSIG4(+) macrophages might play a crucial role in the development of new therapies to prevent T cell suppression in sepsis.

Fatty Acid-Driven Polarization of Suppressive Bone Marrow-Derived Macrophages Including Metabolic and Functional Analysis.

Macrophages represent not only the first line of defense against pathogens and are the main drivers of inflammation but are also involved in the initiation, immune evasion as well as metastasis of tumors. Therefore, it has been suggested that diminishing the immune regulatory function of macrophages would support the natural immune surveillance or antitumor therapies, respectively. However, the plasticity of macrophages represents an obstacle in understanding and manipulating the role of macrophages in tumor tissue or the tumor microenvironment. Here, we describe a protocol to differentiate macrophages, based on changing their metabolic environment, from bone marrow precursors to tumor-associated macrophage-like cells of an immune suppressive phenotype. Based on these protocols, the inhibitory functional phenotype of macrophages can be manipulated and therefore further analyzed as described, by interrupting metabolic pathways.

The interplay of interleukin-17A and breast cancer tumor microenvironment as a novel immunotherapeutic approach to increase tumor immunogenicity.

Based on its known role in mediating tumor progression and the correlation with poor response to chemotherapy, we hypothesized that blocking interleukin-17A (IL-17A) by anti-IL-17 monoclonal antibodies might have the ability to suppress programmed death-ligand-1 (PD-L1) and to modulate the expression and function of myeloid-derived suppressor cells (MDSCs) in BC microenvironment. We also compared the apoptotic activity of anti-IL-17 with those acquired from our previous work on monoclonal antibodies against IL-6. The influence of anti-IL-17 was investigated in two doses on localized freshly resected tissues from 50 patients with BC. Results revealed increased IL-17A in BC tumor tissues versus surrounding tissues. Additionally, PD-L1 expression was inhibited in cultures treated with both doses of anti-IL-17. Frequencies of MDSCs were reduced in those cultures with anti-IL-17 with reduced suppressive activity. The induced apoptosis in the tumor cells was significantly increased. Anti-IL-17 antibodies effect was related to late stages, vascular metastasis, and hormonal status. Results of the current work suggest a promising role for anti-IL-17 monoclonal antibodies in enhancement of anti-tumor immunological activity in BC, potentially involving suppression of immune checkpoint PD-L1 and MDSCs inhibition with a marked response in aggressive disease.

B cells from Patients with Rheumatoid Arthritis Show Conserved CD39-Mediated Regulatory Function and increased CD39 Expression After Positive Response to Therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with increased pro-inflammatory mediators. In inflammatory microenvironments, exogenous ATP (eATP) is hydrolyzed to adenosine, which exerts immunosuppressive effects, by the consecutive action of the ectonucleotidases CD39 and CD73. Mature B cells constitutively express both ectonucleotidases, converting these cells to potential suppressors. Here, we assessed CD39 and CD73 expression on B cells from treated or untreated patients with RA. Neither the frequency of CD73+CD39+ and CD73-CD39+ B cell subsets nor the levels of CD73 and CD39 expression on B cells from untreated or treated RA patients showed significant changes in comparison to healthy controls (HC). CpG+IL-2-stimulated B cells from HC or untreated RA patients increased their CD39 expression, and suppressed CD4+ and CD8+ T cell proliferation and intracellular TNF-production. A CD39 inhibitor significantly restored proliferation and TNF-producing capacity in CD4+ T cells, but not in CD8+ T cells, from HC and untreated RA patients, indicating that B cells from untreated RA patients conserved CD39-mediated regulatory function. Good responder patients to therapy (R-RA) exhibited an increased CD39 but not CD73 expression on B cells after treatment, while most of the non-responder (NR) patients showed a reduction in ectoenzyme expression. The positive changes of CD39 expression on B cells exhibited a negative correlation with disease activity and rheumatoid factor levels. Our results suggest modulating the ectoenzymes/ADO pathway as a potential therapy target for improving the course of RA.

Isolation of Human Circulating Myeloid-Derived Suppressor Cells and Analysis of Their Immunosuppressive Activity.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of myeloid cells with potent immunosuppressive activity and characterized by a pathological state of activation. The T cell suppression assay is the most common method to evaluate the suppressive capacity of MDSC. Identifying the suppressive potential of different MDSC subsets within individual donors is key for understanding the biology of MDSC and their clinical relevance. Here we describe assays to ascertain and quantify the suppression of autologous T cells by human MDSC. These include the dye dilution proliferation assay for flow cytometry and the detection of IFNγ production by T cells using flow cytometry and sandwich ELISA.

TGF-ß Enhances the Anti-inflammatory Effect of Tumor- Infiltrating CD33+11b+HLA-DR Myeloid-Derived Suppressor Cells in Gastric Cancer: A Possible Relation to MicroRNA-494.

BACKGROUND: Accumulation of myeloid-derived suppressor cells (MDSCs) constitutes a key mechanism of tumor immune evasion in gastric cancer (GC). Therefore, searching for more accurate prognostic factors affecting their immunosuppressive role has become a growing interest in cancer immunotherapy research. Increased expression of microRNA-494 was noticed in MDSCs from tumor-bearing mice, suggesting another new therapeutic objective for cancer treatment. It was also discovered that tumor-derived transforming growth factor beta (TGF-ß) is responsible for the up-regulation of microRNA-494 in MDSCs. The purpose of this study was to address the effect of recombinant (rTGF-ß) on the anti-inflammatory activity of MDSCs in GC and its possible association with micro-RNA-494 expression in tumor tissue. METHODS: Freshly obtained GC tumor tissue samples and peripheral blood were used for isolation of CD33+11b+HLADR- MDSCs cells from 40 GC patients and 31 corresponding controls using flow cytometry. MDSCs were co-cultured with isolated autologous T cells to assess proliferation and cytokine production in the presence and absence of rTGF-ß. Real-time PCR and Enzyme linked immunosorbent assay were used to evaluate tumor expression of miRNA-494 and TGF-ß respectively. RESULTS: Results showed that rTGF-ß markedly increased the suppressive ability of tumor MDSCs on proliferation of autologous T cells and interferon gamma production. However, no inhibitory effect was observed for MDSCs from circulation. In addition, infiltration of MDSCs in tumors is associated with the prognosis of GC. MiRNA-494 was also extensively expressed in tumor samples with a significant correlation to MDSCs. CONCLUSION: These results indicate that tumor-derived MDSCs but not circulatory MDSCs have an immunosuppressive effect on T cells, potentially involving TGF-ß mediated stimulation.  Results also suggest a role for miRNA-494 in GC progression. Therefore, control of TGF-ß and miRNA-494 may be used as a treatment strategy to downregulate the immunosuppressive effect of MDSCs.
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Pancreas-derived mesenchymal stromal cells share immune response-modulating and angiogenic potential with bone marrow mesenchymal stromal cells and can be grown to therapeutic scale under Good Manufacturing Practice conditions.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) isolated from various tissues are under investigation as cellular therapeutics in a wide range of diseases. It is appreciated that the basic biological functions of MSCs vary depending on tissue source. However, in-depth comparative analyses between MSCs isolated from different tissue sources under Good Manufacturing Practice (GMP) conditions are lacking. Human clinical-grade low-purity islet (LPI) fractions are generated as a byproduct of islet isolation for transplantation. MSC isolates were derived from LPI fractions with the aim of performing a systematic, standardized comparative analysis of these cells with clinically relevant bone marrow-derived MSCs (BM MSCs). METHODS: MSC isolates were derived from LPI fractions and expanded in platelet lysate-supplemented medium or in commercially available xenogeneic-free medium. Doubling rate, phenotype, differentiation potential, gene expression, protein production and immunomodulatory capacity of LPIs were compared with those of BM MSCs. RESULTS: MSCs can be readily derived in vitro from non-transplanted fractions resulting from islet cell processing (i.e., LPI MSCs). LPI MSCs grow stably in serum-free or platelet lysate-supplemented media and demonstrate in vitro self-renewal, as measured by colony-forming unit assay. LPI MSCs express patterns of chemokines and pro-regenerative factors similar to those of BM MSCs and, importantly, are equally able to attract immune cells in vitro and in vivo and suppress T-cell proliferation in vitro. Additionally, LPI MSCs can be expanded to therapeutically relevant doses at low passage under GMP conditions. CONCLUSIONS: LPI MSCs represent an alternative source of GMP MSCs with functions comparable to BM MSCs.

Approaches to inducing antigen-specific immune tolerance in allergy and autoimmunity: Focus on antigen-presenting cells and extracellular vesicles.

Increasing prevalence of allergic and autoimmune diseases urges clinicians and researchers to search for new and efficient treatments. Strategies that activate antigen-specific immune tolerance and simultaneously maintain immune reactivity to all other antigens deserve special attention. Accordingly, antigen-presenting cells (APCs) seem to be the best suited for orchestrating these mechanisms by directing T cell immune responses towards a tolerant subtype. Recent advances in understanding cell-to-cell communication via extracellular vesicles (EVs) make the latter promising candidates for reprogramming APCs towards a tolerant phenotype, and for mediating tolerogenic APC function. Thus, comprehensive studies have been undertaken to describe the interactions of APCs and EVs naturally occurring during immune tolerance induction, as well as to develop EV-based manoeuvres enabling the induction of immune tolerance in an antigen-specific manner. In this review, we summarize the findings of relevant studies, with a special emphasis on future perspectives on their translation to clinical practice.

LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells.

We recently demonstrated that leukocyte Ig-like receptor 4 (LILRB4) expressed by monocytic acute myeloid leukemia (AML) cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain. The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs (ITIMs); the tyrosines at positions 360, 412, and 442 are phosphorylation sites. Here, we analyzed how the ITIMs of LILRB4 in AML cells mediate its function. Our in vitro and in vivo data show that Y412 and Y442, but not Y360, of LILRB4 are required for T-cell inhibition, and all three ITIMs are needed for leukemia cell infiltration. We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa. The intracellular domain of LILRB4, but not that of LILRB1, mediates T-cell suppression and AML cell migration. Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.

Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGFß.

High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T-cell responses in CRC could inspire novel therapeutic approaches to achieve broader immunotherapy responsiveness. Here, we investigated T cell-suppressive properties of different myeloid cell types in an inducible colon tumor mouse model. The most potent inhibitors of T-cell activity were tumor-infiltrating neutrophils. Gene expression analysis and combined in vitro and in vivo tests indicated that T-cell suppression is mediated by neutrophil-secreted metalloproteinase activation of latent TGFß. CRC patient neutrophils similarly suppressed T cells via TGFß in vitro, and public gene expression datasets suggested that T-cell activity is lowest in CRCs with combined neutrophil infiltration and TGFß activation. Thus, the interaction of neutrophils with a TGFß-rich tumor microenvironment may represent a conserved immunosuppressive mechanism in CRC.