Impair Tumor Immunity Research Articles

CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage

ABSTRACT Cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic heterogeneity, with specific subsets implicated in immunosuppression in various malignancies. However, whether and how they attenuate anti-tumor immunity in gastric cancer (GC) remains elusive. CPT1C, a unique isoform of carnitine palmitoyltransferase pivotal in regulating fatty acid oxidation, is briefly indicated as a protumoral metabolic mediator in the tumor microenvironment (TME) of GC. In the present study, we initially identified specific subsets of fibroblasts exclusively overexpressing CPT1C, hereby termed them as CPT1C+CAFs. Subsequent findings indicated that CPT1C+CAFs fostered a stroma-enriched and immunosuppressive TME as they correlated with extracellular matrix-related molecular features and enrichment of both immunosuppressive subsets, especially M2-like macrophages, and multiple immune-related pathways. Next, we identified that CPT1C+CAFs promoted the M2-like phenotype of macrophage in vitro. Bioinformatic analyses unveiled the robust IL-6 signaling between CPT1C+CAFs and M2-like phenotype of macrophage and identified CPT1C+CAFs as the primary source of IL-6. Meanwhile, suppressing CPT1C expression in CAFs significantly decreased IL-6 secretion in vitro. Lastly, we demonstrated the association of CPT1C+CAFs with therapeutic resistance. Notably, GC patients with high CPT1C+CAFs infiltration responded poorly to immunotherapy in clinical cohort. Collectively, our data not only present the novel identification of CPT1C+CAFs as immunosuppressive subsets in TME of GC, but also reveal the underlying mechanism that CPT1C+CAFs impair tumor immunity by secreting IL-6 to induce the immunosuppressive M2-like phenotype of macrophage in GC.

Single Cell Multi-Omic Dissection of Response and Resistance to Chimeric Antigen Receptor T Cells Against BCMA in Relapsed Multiple Myeloma

Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of relapsed/refractory multiple myeloma (RRMM). Robust variables that predict long-term response are currently missing. Limited data are especially available on the impact of bridging therapies on manufacturing and outcome. We conducted a longitudinal single-cell multi-omics study to identify factors that predict response to BCMA-directed CAR T cells. Changes in the immune microenvironment associated with response were analyzed as well as the impact of prior bridging therapy with bispecific antibodies on subsequent CAR T cell manufacturing and outcome. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 29 consecutive MM patients treated with commercially available anti-BCMA CAR T cells on the day of leukapheresis as well as days 30 and 100 after CAR T cell infusion. PBMCs were subjected to single cell RNA, T-cell receptor (TCR) and B-cell receptor (BCR) sequencing. A custom panel of 57 oligonucleotide-coupled antibodies was used to study surface proteomics. Downstream analyses were performed with Seurat. Differences in cellular compositions at all three time points were analyzed with scCODA. To analyze CAR T cell functionality, CAR T cells from peripheral blood were isolated 7 days after infusion and subjected to an in vitro cytotoxicity assay after expansion and stimulation. Patients were grouped based on their best response following CAR T cell infusion (CR: n=12, non CR: n=17). Results: In total, 375,338 cells were sequenced (median 7246 cells/sample, range 1,569-10,972 cells) and 354,878 cells (94.5%) passed quality assessment. Quantitative and qualitative differences in the cellular composition of peripheral blood between CR and non CR patients were detected at the time of leukapheresis as well as on days 30 and 100 following infusion. CR patients harbored significantly more CD8+ effector memory T cells (TEM) at leukapheresis and less NK cells on day 30 after therapy compared to non CR patients. Regulatory T cells isolated at the time of leukapheresis from non CR patients exhibited significantly higher surface protein levels of CXCR3, CD40, CD95 and KLRG1 (p<0.015, respectively) that have been associated with T cell senescence and impaired tumor immunity. No significant differences in cell numbers between CR and non CR were detected on day 100 after CAR T cell infusion. However, single cell TCR analysis revealed an increasing diversity in the TCR repertoire over time in patients with CR, while Shannon diversity decreased from leukapheresis over day 30 to day 100 in non CR patients (p=0.004). The prior administration of the bispecific antibody teclistamab had no significant impact on the quantitative cellular composition at the time of leukapheresis. However, termination of manufacturing in the first attempt occurred in all patients with a close proximity of teclistimab administration and apheresis. Differential gene expression analysis showed that the application of teclistamab was associated with impaired T cell activation and exhaustion indicated by upregulation of e.g. CTLA4, TIGIT, LAG3 and GZMK. After discontinuation of teclistamab (median 4 weeks) and successful manufacturing of CAR T cells, we found no significant differences for in vitro cytotoxicity and in vivo expansion of CAR T cells. CAR T cells isolated at day 7 post-infusion from patients in CR, non CR or with prior teclistamab exposure, effectively eliminated MM cells (U-266). Tracking of single CAR T cells over time showed that the majority of CAR+ cells were CD8+ TEMs regardless of remission achievement or prior teclistamab exposure. Conclusion: We demonstrate that differences between MM patients achieving a CR and patients with suboptimal response upon anti-BCMA CAR T cell therapy can already be identified at the time of leukapheresis. Long-term changes associated with CR include a diversification of the TCR repertoire. Successful CAR T cell manufacturing is hampered by exposure to bispecific antibodies but can be successfully achieved by allowing for a wash-out phase of ca. 4 weeks.

TEDC2 plays an oncogenic role and serves as a therapeutic target of hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies and tends to have a poor prognosis due to its insidious onset, difficulty in early diagnosis, and limited treatment options. Tubulin epsilon and delta complex 2 (TEDC2), also known as C16orf59, is implicated in maintaining centriole stability, but the involvement of TEDC2 in HCC remains unknown. This study aimed to investigate the expression profile and potential mechanisms of TEDC2 in HCC. MethodsMultiple RNA sequencing datasets were screened for differentially expressed genes in HCC, and the prognosis-related gene, TEDC2, was further screened as a target gene in this study. The expression of TEDC2 in public datasets and clinical specimens was analyzed, and the involvement of TEDC2 in HCC was investigated by bioinformatic analysis and in vitro experiments. ResultsTEDC2 levels were elevated in HCC compared to healthy livers. Overexpression of TEDC2 was positively correlated with pathologic stage and histologic grade. In addition, TEDC2 was found to be an independent prognostic predictor. An excellent prognostic model of HCC was successfully constructed with TEDC2 in combination with the TNM stage. Bioinformatic analysis revealed that overexpression of TEDC2 might be associated with impaired tumor immunity in HCC, as evidenced by increased infiltration of T helper 2 (Th2) cells and reduced infiltration of cytotoxic cells. Further studies showed that TP53 mutations regulated TEDC2 expression, and TEDC2 was significantly associated with drug sensitivity. Moreover, overexpression of TEDC2 promoted cell metastasis and proliferation in vitro. ConclusionThese findings initially suggested a crucial effect of TEDC2 overexpression on HCC tumor progression, suggesting its potential as a novel prognostic and therapeutic target in HCC.

Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer.

Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from patients with PDAC for changes in cDCs. We found that circulating cDC2s and their progenitors were significantly decreased in the blood of patients with PDAC, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in patients with PDAC and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of patients with PDAC showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.

Prognostic and immunological role of acetaldehyde dehydrogenase 1B1 in human tumors: A pan-cancer analysis.

Acetaldehyde dehydrogenases (ALDH) 1B1 is associated with a poor prognosis in pancreatic cancer, colorectal cancer, and osteosarcoma. Overexpression of ALDH also impairs tumor immunity. However, it is unclear how ALDH1B1 is associated with patient prognosis and immune infiltration in different cancer types. This is an original research based on bioinformatics analysis. In this study, we investigated the expression and prognostic value of ALDH1B1 in pan-cancer specimens using several databases, including GEPIA2 and Kaplan-Meier Plotter. The GEPIA2 and TIMER2 databases were used to explore correlations between ALDH1B1 expression and immune infiltration in cancers, especially head and neck squamous cell carcinoma (HNSC) and stomach adenocarcinoma (STAD). Finally, the expression of ALDH1B1 was validated by qPCR and immunohistochemistry. The expression of ALDH1B1 differed in most cancers compared to normal tissue controls. ALDH1B1 has an important impact on the prognosis different cancer types, and the high expression of ALDH1B1 is inversely associated with survival in patients with HNSC. A significant positive correlation was identified between ALDH1B1 expression in HNSC and immune infiltration. The poor prognosis associated with high expression of ALDH1B1 may be related to the promotion of M2 polarization of tumor-associated macrophages. Furthermore, markers of immune cell infiltration, such as exhausted T cells and regulatory T cells showed different patterns of ALDH1B1-associated immune infiltration. ALDH1B1 can serve as a prognostic biomarker in pan-cancer types and is correlated with immune infiltration.

Matrix stiffness-dependent STEAP3 coordinated with PD-L2 identify tumor responding to sorafenib treatment in hepatocellular carcinoma

BackgroundFerroptosis have been implicated in tumorigenesis, tumor progression, and chemo- and immuno-therapy in cirrhotic hepatocellular carcinoma (HCC), indicating its association with matrix stiffness and clinical benefit of targeting drugs or immune checkpoint inhibitor. Here, we postulated that increased matrix stiffness reduces ferroptosis and impairs tumor immunity by regulating the expression of ferroptosis- and immune-related genes in HCC, which might be a robust predictor of therapeutic efficacy.MethodsUsing publicly available tissue microarray datasets, liver cancer rat model, and clinical specimen, ferroptosis-related differential genes in HCV-infected cirrhotic HCC and its mechanical heterogeneous pattern of expression were screened and identified. Further investigation on the underlying mechanism of matrix stiffness-regulated ferroptosis and the expression of immune mediator were performed. Finally, threshold analysis of HCC cases with sorafenib treatment revealed the value of clinical applications of these potential predictors.ResultsSTEAP3 was identified as the ferroptosis-related differential genes in HCV-infected cirrhotic HCC. Stiffer matrix decreased STEAP3 in the invasive front area of HCC and the liver cirrhotic tissue. Contrarily, softer matrix induced STEAP3 in the central area of HCC and the normal liver tissue. Immunological correlation of STEAP3 in cirrhotic HCC showed that STEAP3-mediated immune infiltration of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells and HCC prognosis, predicting to regulate immune infiltration. Overexpression of STEAP3 induced ferroptosis and inhibited the expression of immune mediator of PD-L2 on a stiff matrix. Especially, the ferroptosis- and immune-related gene predictive biomarker (FIGPB), including STEAP3 and PD-L2, predicts better clinical benefit of sorafenib in HCC patients.ConclusionsThis finding identifies matrix stiffness impairs ferroptosis and anti-tumor immunity by mediating STEAP3 and PD-L2. More importantly, coordinated with PD-L2, matrix stiffness-dependent STEAP3 could be applied as the independent predictors to favorable sorafenib response, and thus targeting it could be a potential diagnosis and treatment strategy for HCC.

SLC39A1 Overexpression is Associated with Immune Infiltration in Hepatocellular Carcinoma and Promotes Its Malignant Progression.

BackgroundSolute carrier family 39 member 1 (SLC39A1) has been identified as a zinc ion transport protein that possesses oncogenic properties in various types of cancers. However, its potential function in hepatocellular carcinoma (HCC) remains unknown. This study aimed to investigate the expression profile and potential mechanisms of SLC39A1 in HCC.MethodsSLC39A1 expression was analyzed using multiple databases. The clinical significance and associated biological pathways of SLC39A1 were investigated using bioinformatics analysis. Potential correlations between SLC39A1 expression and tumor immunity in HCC were also evaluated using single-sample gene set enrichment analysis (GSEA). Sixty paired HCC samples were used to verify the expression pattern of SLC39A1. In vitro studies were performed to investigate the oncogenic effects of SLC39A1 in HCC. Western blot analysis was conducted to further investigate the possible involved signaling pathways.ResultsThe overexpression of SLC39A1 in HCC was determined by bioinformatics analysis and was confirmed in tissues from our center. SLC39A1 overexpression was also significantly correlated with worse prognosis, advanced TNM stage, and histological grade. GSEA analysis demonstrated that SLC39A1 overexpression was involved in various tumor-related pathways, such as the cell cycle and Wnt signaling pathway. SLC39A1 knockdown repressed the proliferation, invasion, and migration abilities of HCC cells. Furthermore, SLC39A1 knockdown decreased the expression of the tumor progression-related proteins (eg, cyclin D1 and MMP2) and Wnt signaling pathway-related proteins (eg, Wnt3A and β-catenin). In addition, SLC39A1 overexpression may be associated with impaired tumor immunity in HCC, as evidenced by the increased infiltration of Th2 cells and reduced infiltration of cytotoxic cells.ConclusionThese findings preliminarily suggested the crucial effect of SLC39A1 overexpression on HCC tumor progression and immunosuppression, suggesting its potential as a novel prognostic and therapeutic target in HCC.

High numbers of programmed cell death-1-positive tumor infiltrating lymphocytes correlate with early onset of post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation. In addition to reactivation of Epstein-Barr virus in immunocompromised patients, impaired tumor immunity is suggested to be a risk factor for PTLD. However, it remains unclear whether immune suppressive tumor-infiltrating lymphocytes (TILs) correlate with the occurrence or prognosis of PTLD. We analyzed TILs in 26 patients with PTLD to elucidate the clinicopathological significance of the expression of PD-1 and FoxP3, which are associated with exhausted T-cells and regulatory T-cells (Tregs), respectively. Numbers of PD-1+ TILs in the PTLD specimens were significantly higher in patients who developed PTLD early after transplantation (P = 0.0040), while numbers of FoxP3+ TILs were not (P = 0.184). There was no difference in overall response rate regardless of the expression of PD-1 or FoxP3. FoxP3high patients tended to have a shorter time to progression compared with FoxP3low patients, especially in the case of FoxP3high patients with diffuse large B-cell lymphoma-subtype PTLD (P = 0.011), while PD-1high patients did not. These results suggest that T-cell exhaustion may be mainly associated with PTLD development, while immune suppression by Tregs may be dominant in enhanced progression of PTLD following disease occurrence.

Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization

ABSTRACT A large number of heterogeneous macrophages can be observed in solid tumor lesions. Classically activated M1 macrophages are a powerful killer of cancer cells. In contrast, tumor-associated macrophages (TAMs) are often referred to as M2 phenotype and usually impair tumor immunity mediated by cytotoxic lymphocytes, natural killer (NK) cells and CD8+ T cells. Therefore, orchestrating M2 to M1 reprogramming will provide a promising approach to tumor immunotherapy. Here we used a PyMT-induced spontaneous breast cancer model in which M2-polarized macrophages were abundant. This M2 phenotype was closely related to tumor progression and immune dysfunction of NK cells and CD8+ T cells. We then found that these TAMs showed increased energy expenditure and over-activation of two kinases, Akt and mammalian target of rapamycin (mTOR). Myeloid inactivation of phosphoinositide-dependent kinase-1 (PDK1), the upstream regulator for Akt and mTOR signaling, significantly reduced excessive metabolic activation of macrophages. Notably, the loss of PDK1 significantly led to regression of breast cancer and prevented lung metastasis. Mechanistically, PDK1 deficiency mainly inhibited the activation of mTOR complex 1 (mTORC1), transforming TAMs into M1 phenotype, thereby reversing tumor-related dysfunction of T cells and NK cells. Therefore, targeting PDK1 may be a new approach for M2 macrophage-enriched solid tumor immunotherapy.

DKK2 Impairs Tumor Immunity Infiltration and Correlates with Poor Prognosis in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancer types despite the improvement of modern medicine. In our present study, we found that dickkopf-related protein 2 (DKK2) shares a higher expression in PDAC compared with adjacent pancreas tissue in tissue microarray. In addition, an elevated expression of DKK2 predicts poorer prognosis of patients and positively correlated with poor tumor differentiation. Multivariate Cox regression analysis was also performed and confirmed that the expression of DKK2 is an independent prognostic factor in PDAC. A high expression of DKK2 correlates with cell migration and epithelial mesenchymal transition based on gene set enrichment analysis (GSEA) while knockdown of DKK2 in PDAC cells resulted in impaired cellular migration. Furthermore, GSEA predicts negative correlation between tumor immunity invasion and DKK2 expression. We then confirmed these results and demonstrated that a higher expression of DKK2 imparts the recruitment of CD8+ T cells. Our work suggested that DKK2 imparts tumor immune evasion and is associated with poor prognosis in pancreatic ductal adenocarcinoma.

Pretransplant Cancer in Kidney Recipients in Relation to Recurrent and De Novo Cancer Incidence Posttransplantation and Implications for Graft and Patient Survival.

Whether kidney transplant recipients who were treated for a malignant tumor before transplantation are at an increased risk of developing a tumor posttransplantation has not been adequately quantified and characterized. We studied more than 270 000 patients on whom pretransplant and posttransplant malignancy data were reported to the Collaborative Transplant Study. More than 4000 of these patients were treated for pretransplant malignancy. The posttransplant tumor incidence in these patients was compared to that in recipients without a pretransplant tumor. Cox regression, considering multiple confounders, was applied. Significant increases in posttransplant tumor incidence with hazard ratio ranging from 2.10 to 5.47 (all P < 0.001) were observed for tumors in the site-specific pretransplant locations, suggesting tumor recurrences. There were also significantly increased de novo tumors in new locations with hazard ratio ranging from 1.28 to 1.89. Pretransplant basal cell carcinoma of the skin and male genital cancer were associated with significantly increased death-censored graft survival, suggesting impaired immune responsiveness against transplanted kidneys. Time interval from pretransplant tumor occurrence to transplantation and posttransplant mammalian target of rapamycin inhibitor treatment was not found to be of significant relevance in this study. Patients who experienced a pretransplant tumor are at significant risk of tumor recurrence, regardless of the length of interval between tumor treatment and transplantation. There is also some increased risk for de novo tumors, suggesting impaired immune surveillance. Impaired tumor immunity appears to extend to a lower rate of transplant rejection because patients with pretransplant tumors tended to show improved death-censored graft survival.

Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer

The role of aldehyde dehydrogenase (ALDH) in carcinogenesis and resistance to cancer therapies is well known. Mounting evidence also suggests a potentially important role for ALDH in the induction and function of regulatory T (Treg) cells. Treg cells are important cells of the immune system involved in promoting immune tolerance and preventing aberrant immune responses to beneficial or non-harmful antigens. However, Treg cells also impair tumor immunity, leading to the progression of various carcinomas. ALDH expression and the subsequent production of retinoic acid by numerous cells, including dendritic cells, macrophages, eosinophils and epithelial cells, seems important in Treg induction and function in multiple organ systems. This is particularly evident in the gastrointestinal tract, pulmonary tract and skin, which are exposed to a myriad of environmental antigens and represent interfaces between the human body and the outside world. Expression of ALDH in Treg cells themselves may also be involved in the proliferation of these cells and resistance to certain cytotoxic therapies. Hence, inhibition of ALDH expression may be useful to treat cancer. Besides the direct effect of ALDH inhibition on carcinogenesis and resistance to cancer therapies, inhibition of ALDH could potentially augment the immune response to tumor antigens by inhibiting Treg induction, function and ability to promote immune tolerance to tumor cells in multiple cancer types.

Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance

Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As myeloid cells and conventional dendritic cells (cDCs) are derived from the same progenitors, we postulated that myelopoiesis might impact cDC development. The cDC subset, cDC1, which includes human CD141+ DCs and mouse CD103+ DCs, supports anti-tumor immunity by stimulating CD8+ T-cell responses. Here, to understand how cDC1 development changes during tumor progression, we investigated cDC bone marrow progenitors. We found localized breast and pancreatic cancers induce systemic decreases in cDC1s and their progenitors. Mechanistically, tumor-produced granulocyte-stimulating factor downregulates interferon regulatory factor-8 in cDC progenitors, and thus results in reduced cDC1 development. Tumor-induced reductions in cDC1 development impair anti-tumor CD8+ T-cell responses and correlate with poor patient outcomes. These data suggest immune surveillance can be impaired by tumor-induced alterations in cDC development.

Abstract 1573: The progesterone analogue, Norgestrel, impairs tumor immunity and promotes metastatic breast cancer progression

Abstract The immune system is responsible for recognition and elimination of cancer cells. Tumors, however, can elicit different evasive mechanisms that contribute to immune escape Thus, understanding the immunosuppressive pathways that hamper tumor immunity is critical for the identification of novel therapeutic targets. Progestin-containing hormonal supplementation (as hormone replacement therapy or contraceptive) has been associated with an increase in the risk of breast cancer incidence and recurrence. Moreover, progesterone, as a natural hormone, generally impairs cellular immune responses responsible of preventingfetal rejection during pregnancy. We postulated that progestins and in particular the widely used contraceptive Norgestrel may impair tumor immunity and foster immunosuppressive tumor microenvironments. We injected Balb/c mice with the triple-negative 4T1breast tumor,, and treated them with a Norgestrel releasing depot for 30 days. Norgestrel-treated mice displayed a higher frequency of suppressive regulatory T cells (Tregs) in draining lymph nodes and tumors which displayed a CD4+CD25+Foxp3+CD44+ phenotype. Accordingly, norgestrel-treated mice showed greater number of exhausted PD1+ Tim-3+ CD8 T cells in the tumor microenvironment. Furthermore, in vitro exposure to Norgestrel also promoted differentiation and expansion of Tregs which activated the mTOR pathway assessed by phosphorylation of S6 ribonucleoprotein. These effects could not be prevented by the progesterone nuclear receptor antagonist, Zk 230211, suggesting that Norgestrel acts preferentially through membrane progesterone receptors. Although no significant difference regarding tumor growth could be observed, Norgestrel-treated mice showed greater number of lung metastasis. Mechanistically, Norgestrel-driven Treg cells showed increased expression of RANKL, a protein involved in breast cancer development and progression. Our results identify a novel progestin-mediated tumor-promoting mechanism and indicate caution onthe use of Norgestrel-supplementation therapies. Our findings suggest that Norgestrel may impair tumor immunity, thereby promoting metastatic dissemination of breast cancer cells. Citation Format: Tomas Dalotto Moreno, Gabriel Adrian Rabinovich, Mariana Salatino. The progesterone analogue, Norgestrel, impairs tumor immunity and promotes metastatic breast cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1573.

Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity.

IFNγ is a cytokine that plays a pivotal role in antitumor host immunity. IFNγ elicits potent antitumor immunity by inducing Th1 polarization, CTL activation, and dendritic cell tumoricidal activity. However, there are significant discrepancies in our understanding of the role of IFNγ as an antitumor cytokine. In certain circumstances, IFNγ obviously acts to induce tumor progression. IFNγ treatment has negatively affected patient outcomes in some clinical trials, while it has favorably affected outcomes in other trials. Several mechanisms, including IFNγ insensitivity and the downregulation of the MHC complex, have been regarded as the reasons for this discrepancy, but they do not fully explain it. We propose IFNγ-induced programmed cell death 1 ligand 1 (PD-L1) expression as a novel mechanism by which IFNγ impairs tumor immunity. When tumor cells encounter CTLs in the local environment, they detect them via the high concentration of IFNγ secreted from CTLs, which induces PD-L1 expression in preparation for an immune attack. Thus, tumor cells acquire the capability to counterattack immune cells. These findings indicate that although IFNγ is thought to be a representative antitumor cytokine, it actually has dual roles: one as a hallmark of antitumor immunity and the other as an inducer of the immune escape phenomenon through various mechanisms, such as PD-L1 expression. In this context, the optimization of immunotherapy according to the local immune environment is important. Anti-PD-1/PD-L1 treatment may be particularly promising when efficient tumor immunity is present, but it is disturbed by PD-L1 expression. Clin Cancer Res; 22(10); 2329-34. ©2016 AACR.

Fas Ligand Deficiency Impairs Tumor Immunity by Promoting an Accumulation of Monocytic Myeloid-Derived Suppressor Cells.

The Fas receptor ligand FasL regulates immune cell levels by inducing apoptosis of Fas receptor-positive cells. Here, we studied the impact of host FasL on tumor development in mice. Genetically targeting FasL in naïve mice increased myeloid cell populations, but, in marked contrast, it reduced the levels of myeloid-derived suppressor cells (MDSC) in mice bearing Lewis lung carcinoma tumors. Analysis of the MDSC subset distribution revealed that FasL deficiency skewed cell populations toward the M-MDSC subset, which displays a highly immunosuppressive activity. Furthermore, tumor-bearing mice that were FasL-deficient displayed an enhanced proportion of tumor-associated macrophages and regulatory T cells. Overall, the immunosuppressive environment produced by FasL targeting correlated with reduced survival of tumor-bearing mice. These results disclose a new role for FasL in modulating immunosuppressive cells.

Circulating peripheral blood mononuclear cells exhibit altered miRNA expression patterns in pancreatic cancer

Evaluation of: Wang WS, Liu LX, Li GP et al. Combined serum CA19-9 and miR-27a-3p in peripheral blood mononuclear cells to diagnose pancreatic cancer. Cancer Prev. Res. (Phila.) 6(4), 331–338 (2013).Patients with pancreatic ductal adenocarcinoma (PDAC) have a bleak outlook, primarily because tumors are detected late and are often too advanced for surgical resection. In addition, these lesions are incredibly resistant to anticancer therapies. The majority of PDAC patients have impaired tumor immunity, contributing to disease development and progression, although the mechanisms remain poorly understood. miRNAs are important negative gene regulators that have critical roles in human tumorigenesis. Blood-based miRNAs have been investigated as biomarkers for various cancers, in the hope that these will outperform current serum tumor markers. The evaluated study examined the miRNA profiles in peripheral blood mononuclear cells from PDAC patients. The theory is that circulating blood cells monitor the patients’ physiological state and respond by altering their transcriptome and that this can then be used to detect disease. In this article, we have examined the evidence for using circulating miRNAs to diagnose/prognose PDAC.

Deficiency in IL-4Rα signaling is associated with impaired tumor immunity (P2057)

Abstract We recently made a seminal observation that Ym1, a chitinase-like lectin, activates NK cells, thereby promoting robust anti-tumor responses in vivo. This activation requires dendritic cells. We next sought to characterize the significance of endogenously expressed Ym1 in tumor immunity. In previous studies, Ym1 has been described as a marker for alternatively activated macrophages. Furthermore, the Th2-associated cytokines IL-4 and IL-13 were shown to induce Ym1 expression in macrophages. From these data, we hypothesized that IL-4Rα-/- mice are deficient in Ym1 and therefore more susceptible to tumor metastasis and growth. Indeed, IL-4Rα-/- mice exhibited reduced serum levels of Ym1. When WT or IL-4Rα-/- mice were i.v. challenged with the allogeneic murine melanoma cell line B16-F1, we observed a 12-fold increase in tumor burden in the lungs of IL-4Rα-/- mice compared to WT mice. Next, we generated bone marrow chimeras in which IL-4Rα-/- mice were adoptively transferred with either WT or IL-4Rα-/- bone marrow cells. Subsequently, the mice were challenged with B16-F1 cells and tumor burden evaluated after two weeks. Mice that received WT bone marrow exhibited significantly fewer tumor nodules in the lungs compared to control mice. In addition, their serum levels of Ym1 had been restored by the introduction of WT bone marrow cells. Altogether, these data indicate that IL-4 is important for tumor immunity via the induction of Ym1.

Delayed wound healing and impaired tumor immunity in mice with lymphatic dysfunction

Delayed wound healing and impaired tumor immunity in mice with lymphatic dysfunction

Title: HMGB1 both enhances and blocks myeloid-derived suppressor cell potency Katherine H. Parker, Suzanne Ostrand-Rosenberg Department of Biological Sciences, University of Maryland Baltimore County, Baltimore MD 21250 (162.40)

Abstract Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate in individuals with cancer and inflammation and play a pivotal role in tumor immunity by suppressing T-cell activation and secreting proinflammatory molecules. MDSC potency is mediated by immune suppressive factors such as inducible NO synthase (iNOs), arginase, and reactive oxygen species (ROS). MDSC also impair tumor immunity through crosstalk with macrophages in which IL-10 production increases while IL-12 production decreases, causing a shift in innate and adaptive immunity towards a type 2 tumor-promoting phenotype. Nuclear protein, High Mobility Group Box1 (HMGB1) is the second most abundant protein within a cell and is released from myeloid cells as a danger response to sepsis, infection, or arthritis. It’s release promotes inflammatory responses. HMGB1 signals through a multitude of receptors including TLR4 and RAGE, which are expressed by MDSC. In contrast to other inflammatory mediators which increase MDSC potency, HMGB1 reduced the suppressive mechanisms of TLR4-\- and wildtype MDSC, by reducing ROS in TLR4-\- MDSC and iNOs levels in wildtype MDSC. Glycyrrhizin, an HMGB1 inhibitor, decreased IL-10 in co-cultures of macrophages and MDSC. These findings suggest that HMGB1 plays both anti- and pro-inflammatory roles in regulating MDSC suppressive activity.