Response In Various Malignancies Research Articles

Chronic Lymphocytic Thyroiditis with Oncocytic Metaplasia Influences PD-L1 Expression in Papillary Thyroid Carcinoma.

Despite the increasing recognition of PD-L1 as predictor of immunotherapeutic response in various malignancies, its role and prognostic significance in thyroid cancer remain underexplored and subject to debate. This study begins to address this gap by comprehensively analyzing PD-L1 expression in papillary thyroid carcinoma (PTC) and investigating its correlation with key clinicopathological variables. We conducted immunohistochemistry (IHC) to assess PD-L1 expression in whole-tissue sections from 121 primary papillary thyroid carcinoma (PTC) cases. We then analyzed the correlations between PD-L1 expression and various clinicopathological variables. PD-L1 expression was detected in 33.1% of papillary thyroid carcinomas (PTCs), predominantly exhibiting weak to moderate intensity. Notably, this study found no significant correlation between PD-L1 expression and various clinicopathological variables. The lack of association with traditional factors such as age, sex, histological subtype, and tumor size suggests the complex and multifaceted nature of PD-L1 regulation in PTC. Multivariate logistic regression analysis identified chronic lymphocytic thyroiditis with oncocytic metaplasia as the sole independent predictor of PD-L1 expression (P = 0.014), underlining the potential influence of the tumor microenvironment on immune checkpoint expression in PTC. Our study underscores the intricate interplay between chronic lymphocytic thyroiditis with oncocytic metaplasia and PD-L1 expression in papillary thyroid carcinoma. The observed link suggests a potential avenue for therapeutic intervention using anti-PD-1/PD-L1 therapies in surgery-refractory PTC. Understanding the dynamics of immune checkpoint regulation in the context of the tumor microenvironment is crucial for devising effective treatment strategies. Future research endeavors should delve deeper into the molecular mechanisms underlying this interaction and explore its implications for patient outcomes. As the field of immunotherapy continues to evolve, our findings contribute valuable insights into the complex immunological landscape of thyroid cancer.

Dynamic peripheral blood immune cell markers for predicting the response of patients with metastatic cancer to immune checkpoint inhibitors

PurposeImmune checkpoint inhibitors (ICIs) have shown durable responses in various malignancies. However, the response to ICI therapy is unpredictable, and investigation of predictive biomarkers needs to be improved.Experimental designIn total, 120 patients receiving ICI therapy and 40 patients receiving non-ICI therapy were enrolled. Peripheral blood immune cell markers (PBIMs), as liquid biopsy biomarkers, were analyzed by flow cytometry before ICI therapy, and before the first evaluation. In the ICI cohort, patients were randomly divided into training (n = 91) and validation (n = 29) cohorts. Machine learning algorithms were applied to construct the prognostic and predictive immune-related models.ResultsUsing the training cohort, a peripheral blood immune cell-based signature (BICS) based on four hub PBIMs was developed. In both the training and the validation cohorts, and the whole cohort, the BICS achieved a high accuracy for predicting overall survival (OS) benefit. The high-BICS group had significantly shorter progression-free survival and OS than the low-BICS group. The BICS demonstrated the predictive ability of patients to achieve durable clinical outcomes. By integrating these PBIMs, we further constructed and validated the support vector machine-recursive and feature elimination classifier model, which robustly predicts patients who will achieve optimal clinical benefit.ConclusionsDynamic PBIM-based monitoring as a noninvasive, cost-effective, highly specific and sensitive biomarker has broad potential for prognostic and predictive utility in patients receiving ICI therapy.

Inflammasome-Primed Myeloid Cells Maintain a Pro-Tumor Microenvironment in Multiple Myeloma

Background: Multiple myeloma (MM) disease progression is influenced by signals from the bone marrow (BM) microenvironment. Recently, we showed that the MM BM is characterized by inflammatory mesenchymal stromal cells (iMSCs) that transcribe MM survival factors and are predicted to recruit proliferating myeloma cells via CCL2-CCR2 interactions (de Jong et al. Nat Immunol. 2021). iMSCs also transcribed high levels of chemokines that can bind to CXCR1 and 2. Myeloid cells are known to express CXCR1/2, and have been implicated in both pro- and anti-tumor responses in various malignancies. Therefore, we hypothesized that iMSCs attract and influence myeloid populations in the MM BM.Results: Using flow cytometry, we verified expression of CXCR1/2 on myeloid cell populations in the BM of 5 newly diagnosed MM (NDMM) patients. CD15 + neutrophils were the most dominant population expressing these receptors, as 22.4% (± 9.8%) of cells expressed CXCR2 alone, and 72.6% (± 8.0%) expressed both CXCR1 and CXCR2. CD14 + monocytes only expressed CXCR2 (86.9% ± 15.8%). Importantly, less than 1% of myeloma cells expressed these receptors (n = 17 NDMM).As these findings suggested neutrophils and monocytes as potential targets of iMSC-mediated chemotaxis, we set out to identify MM-associated alterations in this population by performing single cell RNA sequencing of the full neutrophilic and monocytic lineages (n = 5 NDMM and 2 controls). In line with our flow cytometric data, CXCR1 transcripts were absent in monocytes, while CXCR2 was transcribed by classical monocytes of both myeloma patients and controls. Interestingly, CXCR1 and CXCR2 transcription was increased in mature neutrophils of MM patients compared to controls. Additionally, both mature classical monocytes as well as mature neutrophils of MM patients had an activated transcriptome as defined by increased transcription of C3AR1, SLPI, and IL6R, the plasma cell supportive factor TNFSF13B (encoding BAFF), and the inflammatory cytokines IL1B and IL18. Transcription of IL1B and IL18 can be regulated by pattern-recognition receptors (PRRs) binding damage-associated molecular patterns (DAMPs) resulting from e.g. matrix breakdown. Transcription of PRRs as TLR1, 2 and 4 was increased in mature neutrophils and classical monocytes of MM patients compared to controls. Secretion of IL-1β and IL-18 relies on the cleavage of pro-forms of these cytokines by the inflammasome, a multiprotein complex that is assembled in response to alarmins. Transcription of inflammasome components PYCARD, NLRP3 and CASP1 was increased in mature neutrophils and classical monocytes of patients with MM. Additionally, protein levels of both IL-18 and IL-1β are increased in BM plasma from MM patients, implicating activated neutrophils and monocytes as a potential sources of these cytokines.Conclusion: In MM, mature neutrophils and classical monocytes are activated and might interact with iMSCs via CXCR1 and/or 2. Moreover, these myeloid cells are inflammasome-primed and are likely to be sources of the increased IL-1β levels in the MM BM. Therefore, myeloid cells and iMSCs may form a feed-forward loop in which myeloid cells contribute to a pro-MM environment by maintaining iMSC and by directly providing BAFF to tumor cells. DisclosuresBroyl: Celgene/BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Sonneveld: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

P-069: Inflammasome-primed neutrophils maintain a pro-tumor microenvironment in Multiple Myeloma

<h3>Background</h3> Multiple myeloma (MM) disease progression is influenced by signals from the bone marrow (BM) microenvironment. Recently, we showed that the MM BM is characterized by inflammatory mesenchymal stromal cells (iMSCs) that transcribe MM survival factors and are predicted to recruit proliferating myeloma cells via CCL2-CCR2 interactions (de Jong et al. Nat Immunol. 2021). iMSCs also transcribed high levels of chemokines that can bind to CXCR1 and 2. Myeloid cells are known to express CXCR1/2, and have been implicated in both pro- and anti-tumor responses in various malignancies. Therefore, we hypothesized that iMSCs attract and influence myeloid populations in the MM BM. <h3>Methods</h3> Using flow cytometry, we verified expression of CXCR1/2 on myeloid cell populations in the BM of 5 newly diagnosed MM (NDMM) patients. <h3>Results</h3> CD15+ neutrophils were the most dominant population expressing these receptors, as 22.4% (± 9.8%) of cells expressed CXCR2 alone, and 72.6% (± 8.0%) expressed both CXCR1 and CXCR2. CD14+ monocytes only expressed CXCR2 (86.9% ± 15.8%). Importantly, less than 1% of myeloma cells expressed these receptors (n = 17 NDMM). As these findings suggested neutrophils as a potential target of iMSC-mediated chemotaxis, we set out to identify MM-associated alterations in this population by performing single cell RNA sequencing of the full neutrophilic lineage (n = 5 NDMM and 2 controls). Interestingly, CXCR1 and CXCR2 transcription was increased in mature neutrophils of MM patients compared to controls. Additionally, mature neutrophils of MM patients had an activated transcriptome as defined by increased transcription of C3AR1, SLPI, and IL6R, the plasma cell supportive factor TNFSF13B (encoding BAFF), and the inflammatory cytokines IL1B and IL18. Transcription of IL1B and IL18 can be regulated by pattern-recognition receptors (PRRs) binding damage-associated molecular patterns (DAMPs) resulting from e.g. matrix breakdown. Transcription of PRRs as TLR1, 2 and 4 was increased in mature neutrophils of MM patients compared to controls. Secretion of IL-1 β and IL-18 relies on the cleavage of pro-forms of these cytokines by the inflammasome, a multiprotein complex that is assembled in response to alarmins. Transcription of inflammasome components PYCARD, NLRP3 and CASP1 was increased in mature neutrophils of patients with MM. Additionally, protein levels of both IL-18 and IL-1 β are increased in BM plasma from MM patients, implicating activated neutrophils as a potential source of these cytokines. <h3>Conclusion</h3> In MM, mature neutrophils are activated and might interact with iMSCs via CXCR1/2. Moreover, neutrophils are inflammasome-primed and are likely to be a source of increased IL-1 β levels in the MM BM. As IL-1 β can activate normal MSCs to become iMSC, neutrophils and iMSCs may form a feed-forward loop in which activated neutrophils contribute to a pro-MM environment by maintaining iMSC and by directly providing BAFF to tumor cells.

Exploration of the relationship between tumor mutation burden and immune infiltrates in colon adenocarcinoma

Background: Tumor mutation burden (TMB) was correlated with the immunotherapeutic response in various malignancies. We aimed to evaluate the TMB immune signature in colon adenocarcinoma (COAD).Methods: Gene expression profile, mutation and clinical data of COAD patients were obtained from The Cancer Genome Atlas (TCGA) database. The samples were divided into high and low TMB level groups to identify differentially expressed genes (DEGs). Functional enrichments analyzes were performed to identify the biological functions of the DEGs. Then, immune cell infiltration signatures were calculated by the CIBERSORT algorithm. Finally, Cox proportional hazard model was constructed to estimate the prognostic value of the identified immune-related genes.Results: Gene set enrichment analysis in the high-TMB level group showed that DEGS were enriched in immune-related pathways, such as antigen processing and presentation, Toll-like receptor signaling and natural killer cell-mediated cytotoxicity. A higher infiltration level of CD8+ T cells, CD4+ T cells, activated NK cells , M1 Macrophages and T follicular helper cells was observed in the high-TMB level group. Furthermore, a Cox regression model combined with survival analysis based on the expression level of four identified prognostic genes was constructed, validated anf revealed that higher risk-score levels conferred poor survival outcomes in COAD patients.Conclusions: Our data demonstrate that the high TMB levels are associated with an immune signature in COAD and deepen the molecular understanding of TMB function in tumor immunotherapy.

Role of taurine, its haloamines and its lncRNA TUG1 in both inflammation and cancer progression. On the road to therapeutics? (Review).

For one century, taurine is considered as an end product of sulfur metabolism. In this review, we discuss the beneficial effect of taurine, its haloamines and taurine upregulated gene 1 (TUG1) long non-coding RNA (lncRNA) in both cancer and inflammation. We outline how taurine or its haloamines (N-Bromotaurine or N-Chlorotaurine) can induce robust and efficient responses against inflammatory diseases, providing insight into their molecular mechanisms. We also provide information about the use of taurine as a therapeutic approach to cancer. Taurine can be combined with other chemotherapeutic drugs, not only mediating durable responses in various malignancies, but also circumventing the limitations met from chemotherapeutic drugs, thus improving the therapeutic outcome. Interestingly, the lncRNA TUG1 is regarded as a promising therapeutic approach, which can overcome acquired resistance of cancer cells to selected strategies. In this regard, we can translate basic knowledge about taurine and its TUG1 lncRNA into potential therapeutic options directed against specific oncogenic signaling targets, thereby bridging the gap between bench and bedside.

Serum γ-Glutamyltransferase as a Prognostic Biomarker in Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide.

Serum γ-glutamyltransferase (GGT) is reportedly associated with survival and therapeutic response in various malignancies; however, as far as we are aware its impact on metastatic castration-resistant prostate cancer (mCRPC) has never been assessed. Fifty consecutive men with mCRPC receiving enzalutamide at a single cancer center were retrospectively evaluated. The primary endpoint was overall survival (OS) and the secondary endpoints were prostate-specific antigen (PSA) response, maximal PSA change, and PSA progression-free survival (PSA-PFS). Multivariable analysis demonstrated that elevation of GGT (≥40 U/l) was significantly and independently associated with shorter OS (hazard ratio(HR)=3.61; p=0.004), as were lower hemoglobin (HR=6.04; p<0.001) and higher PSA (HR=4.38; p=0.009). Elevated GGT was also associated with poorer PSA response, maximal PSA change, and shorter PSA-PFS. Elevated GGT was an adverse prognostic indicator in men with mCRPC receiving enzalutamide. External validations would improve the generality of our findings.

Abstract 1249: MLN4924, a protein neddylation inhibitor, induces apoptosis via endoplasmic reticulum (ER)-stress in human cervical cancer

Abstract Cervical cancer is the second most common cancer among the women worldwide. The treatment of the cervical cancer includes the surgery, chemotherapy, external and intracavitary radiotherapy adjusted to the different cancer stage. Despite these treatments, a certain proportion of women still die of the cancer due to recurrent or chemoresistent disease. The toxicity and side effect of these therapies are substantial. Therefore, it is important to develop new drugs or combination treatments to improve patient survival and minimize side effect of the therapy. MLN4924 is an inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit anti-tumor response in various malignancies. In this study, we aim to investigate the anti-tumor effect of MLN4924 on human cervical cancer and underlying mechanism in vitro and in vivo. We used two different grade human bladder cervical cell lines: ME-180 and HeLa. After exposing to MLN4924, the cell viability and apoptosis were measured by MTT and flow cytometry with annexin V-FITC labeling. The efficacy of cell proliferation was determined by BrdU incorporation assay. The cell cycle regulators, cell death-related molecules, and ER stress-related proteins were examined by Western blotting. We also use Nu/Nu xenograft mice model to clarify the effect of MLN4924 on tumor growth in vivo. We demonstrated that MLN4924 effectively induces dose-dependent cytotoxicity, apoptosis and anti-tumor phenomenon in cervical cancer cells. MLN4924 also activate cleaved-Bid, phospho-histone H2A.X, caspases and PARP, decresed phospho-Bcl2, and cause cell cycle arrest. Furthermore, MLN4924 possessed the ability to activate ER stress-related moleculors caspase-4, and CCAAT/enhancer binding protein homologous protein (CHOP), which were involved in UC cell apoptosis, and other stress responses (JNK and c-Jun activations). Moreover, we confirmed MLN4924 inhibited tumor growth and induced ER-stress in a cervical cancer xenograft mice model. Taken together, we demonstrated that MLN4924 induces cytotoxicity and cell cycle retardation, as well as activation of ER stress responses in human cervical cancer. The anti-tumor effect of MLN4924 provides a novel implication in clinical treatment of cervical cancer. Citation Format: Kuan-Lin Kuo, Yeong-Shiau Pu, I-LIN Ho, Chen-Hsun Hsu, Ju-Ton Hsieh, Wei-Chou Lin, Chien-Tso Chou, Kuo-How Huang. MLN4924, a protein neddylation inhibitor, induces apoptosis via endoplasmic reticulum (ER)-stress in human cervical cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1249. doi:10.1158/1538-7445.AM2015-1249