Immunotherapy Targeting PD-1 Research Articles

Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.

11549 Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099.

Abstract 7612: Genetic predictors of anti-PD(L)-1 therapy response in hepatocellular carcinoma

Abstract Introduction: Immunotherapy targeting PD-1/PD-L1 shows promise in treating hepatocellular carcinoma (HCC), but standard predictors like PD-L1 expression are unreliable for gauging treatment response. RNA sequencing has identified a BMS 4-gene inflammatory signature that could more accurately forecast clinical outcomes. However, genomic alterations and tumor mutational burden (TMB) haven't consistently predicted anti-PD(L)-1 therapy response in HCC. Therefore, the aim of this research is to identify potential genetic alternation that could serve as predictive marker for anti-PD(L)-1 therapy responses in advanced HCC. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissues from 38 HCC patients were analyzed using targeted next-generation sequencing with the ACTOncoTM panel before anti-PD(L)-1 therapy. This analysis identified somatic variants across 440 genes and calculated TMB. In silico tools like NetMHC and IEDB predicted neo-peptide-HLA class I binding affinity. Additionally, peripheral blood mononuclear cells provided germline data for paired TMB calculations, with tumor responses assessed by RECIST criteria. Results: Within a cohort of 167 patients with HCC undergoing ICI therapy, 35 (20.9%) responded to treatment, while 132 (79.1%) did not. Available formalin-fixed paraffin-embedded (FFPE) samples from this population included those from 14 responders and 30 non-responders. After conducting quality control measures, which assessed tumor purity, DNA quantity and integrity, as well as sequencing quality, 13 samples from responders and 25 from non-responders qualified for further analysis. Gene alteration analysis identified mutations in TP53 (47%), MUC16 (34%), CTNNB1 (32%), USH2A (16%), ARID1A (13%), NOTCH3 (13%), and ADAMTS16 (11%) of the cases. A TP53 mutation was linked to poor overall survival, whereas mutations in CTNNB1 and the RTK/RAS/RAF pathway did not correlate with clinical outcomes. The median TMB, predicted at 3.2 ± 4.3 mutations per megabase (muts/Mb), was nominally higher in patients who achieved disease control compared to non-responders (4.6 vs. 3.7 muts/Mb, p=0.53). Utilizing paired TMB analysis, those with disease control exhibited a higher TMB trend than non-responders (6.0 vs. 2.2 muts/Mb, p=0.06). Notably, the 13 cases with MUC16 mutations were associated with a significantly higher predicted TMB (10.0 vs. 3.3 muts/Mb, p=0.0015). Conclusions: This study suggests that certain genetic alterations, especially TP53 mutations, may have predictive value for the response to anti-PD(L)-1 therapy in HCC. Moreover, an elevated TMB, particularly when associated with MUC16 mutations, seems to be correlated with improved disease control. Citation Format: San-Chi Chen, Nai-Jung Chiang, MingHuang Chen, Muh-Hwa Yang. Genetic predictors of anti-PD(L)-1 therapy response in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7612.

Abstract 2527: PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a reactive oxygen species (ROS) producing enzyme in gastric cancers

Abstract Immune checkpoint inhibitors have shown outstanding activities in some cancers, but their efficacy is rather variable with limited long-term response in most patients while others do not respond well or even develop resistances. The oxidative state of the tumor and its microenvironment plays a critical role in this response and highlights the importance of better understanding the role of redox enzymes in response to immunotherapy. In fact, Reactive Oxygen Species (ROS) effectors can either up or down regulate PD-L1 expression depending on their targets and mechanisms of action. Our data indicate that DUOX2, an NADPH enzyme involved in the production of H2O2, is expressed in about forty percent of human gastric cancers and is significantly increased in esophageal cancers. Moreover, DUOX2 expression in human gastric and esophageal cancer cells corresponds to down regulation of the immune checkpoint PD-L1. Conversely, down regulation of DUOX2 increases PD-L1, HIF-1α and c-Myc expression in these cells. To better understand the role of DUOX2 in the production of ROS and how it interferes with the expressions of HIF-1α and PD-L1, we also evaluated its effects on the ROS scavenger glutathione (GSH) and the ROS generating Ceramide in cells expressing or not DUOX2. The down regulation of DUOX2 reduced by more than half Ceramide levels and significantly increased GSH levels. This is consistent with the known effect of H2O2 on Ceramide generation through sphingomyelin hydrolysis and H2O2 inhibitory effect on HIF-1α binding and accumulation of HIF-1α protein. Because HIF-1α is a known regulator of PD-L1, DUOX2 expression on some tumors could thus interfere with PD-L1 expression through generation of H2O2. Moreover, because HIF-1α and PD-L1 expression contribute to radio-resistance, DUOX2 expression could sensitize cancer cells to radiation therapy. On the other hand, tumors lacking DUOX2 expression would be expected to be more sensitive to immunotherapy targeting PD-1 and/or PD-L1. DUOX2 expression thus appears to hold significant potential as a valuable biomarker to guide therapeutic decisions regarding radiation or immuno-therapy. Citation Format: France Carrier, Mariana B. Martins. PD-L1 regulation by Dual Oxygenase 2 (DUOX2), a reactive oxygen species (ROS) producing enzyme in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2527.

Genetic and pharmaceutical targeting of HIF1α allows combo-immunotherapy to boost graft vs. leukemia without exacerbation graft vs. host disease

Despite potential impact on the graft vs. leukemia (GVL) effect, immunotherapy targeting CTLA-4 and/or PD-1 has not been successfully combined with bone marrow transplant (BMT) because it exacerbates graft vs. host disease (GVHD). Here, using models of GVHD and leukemia, we demonstrate that targeting hypoxia-inducible factor 1α (HIF1α) via pharmacological or genetic approaches reduces GVHD by inducing PDL1 expression on host tissue while selectively inhibiting PDL1 in leukemia cells to enhance the GVL effect. More importantly, combination of HIF1α inhibition with anti-CTLA-4 antibodies allows simultaneous inhibition of both PDL1 and CTLA-4 checkpoints to achieve better outcomes in models of mouse and human BMT-leukemia settings. These findings provide an approach to enhance the curative effect of BMT for leukemia and broaden the impact of cancer immunotherapy.

N6-Methyladenosine (m6A) Reader IGF2BP1 Accelerates Gastric Cancer Development and Immune Escape by Targeting PD-L1.

N6-methyladenosine (m6A) functions as an important regulator in various human cancers, including gastric cancer. The immunotherapy targeting PD-1/PD-L1 has brought hope for advanced gastric cancer therapeutic. Here, present research aims to investigate the roles of m6A reader IGF2BP1 on gastric cancer tumor development and immune escape. Results indicated that IGF2BP1 up-regulated in the gastric cancer tissue and correlated with poor prognosis of gastric cancer patients. IGF2BP1 overexpression augmented the proliferation of co-cultured gastric cancer cells, and mitigated the CD8+ T cells mediated anti-tumor response, including IFN-γ secretion, surface PD-L1 level, and cytotoxicity of CD8+ T cells. Meanwhile, IGF2BP1 silencing exerted the opposite effects. In silico analysis revealed that there was a remarkable m6A modified site on PD-L1 mRNA. Moreover, the IGF2BP1 overexpression enhanced the stability of PD-L1 mRNA, thereby deteriorating the immune escape of gastric cancer cells. Collectively, these results describe a novel regulatory mechanism of IGF2BP1 by regulating PD-L1 through m6A epigenetic modification, which might provide insights for gastric cancer immunotherapies.

PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models

Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.

PD-1/PD-L1 axis in organ fibrosis.

Fibrosis is a pathological tissue repair activity in which many myofibroblasts are activated and extracellular matrix are excessively accumulated, leading to the formation of permanent scars and finally organ failure. A variety of organs, including the lung, liver, kidney, heart, and skin, can undergo fibrosis under the stimulation of various exogenous or endogenous pathogenic factors. At present, the pathogenesis of fibrosis is still not fully elucidated, but it is known that the immune system plays a key role in the initiation and progression of fibrosis. Immune checkpoint molecules are key regulators to maintain immune tolerance and homeostasis, among which the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis has attracted much attention. The exciting achievements of tumor immunotherapy targeting PD-1/PD-L1 provide new insights into its use as a therapeutic target for other diseases. In recent years, the role of PD-1/PD-L1 axis in fibrosis has been preliminarily explored, further confirming the close relationship among PD-1/PD-L1 signaling, immune regulation, and fibrosis. This review discusses the structure, expression, function, and regulatory mechanism of PD-1 and PD-L1, and summarizes the research progress of PD-1/PD-L1 signaling in fibrotic diseases.

Abstract 6043: Manipulation of mitochondrial metabolism, through SIRT3 agonists, in a novel immunoreactive melanoma organoids model

Abstract The interplay between tumor cell metabolism and immune cells in the tumor microenvironment has emerged as a determinant factor in cancer progression and treatment. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that modulates ROS levels and governs many enzymes that regulate mitochondrial metabolism and homeostasis. SIRT3 has a dual role in cancer; it is regarded as an oncogene and tumor suppressor gene simultaneously. It has tumor-promoting action via keeping ROS levels low and favoring cell proliferation; on the contrary, it can trigger cell death under stress conditions by modulating tumor cell glycolysis. Recent data suggest a role for SIRT3 in cancer immunology with PD-L1 levels are found to be inversely associated with SIRT3 level in cervical cancer, and CD8+ T cells from SIRT3 knockout donor mice exhibited low GVHD in recipients. In this study, we explored the potential role of SIRT3 agonists in sensitizing the immunoreactivity of melanoma cells in a novel immunoreactive melanoma organoids model. We used the B16-F10 melanoma cell line spheroids to determine the effects of SIRT3 agonists on cellular viability, using an ATP assay. Validation of SIRT3 expression was determined via Western blot. Non-toxic amounts of SIRT3 agonists were also applied to melanoma organoids prepared from patient-derived metastatic melanoma from a lymph node. Preliminary results revealed a significant decrease in the viability of the organoids treated with R-propranolol (20µM) and Imipramine blue (0.25µM) agonists. We further investigated the effect of SIRT3 agonists R-propranolol and Imipramine blue on immunotherapy targeting PD-1, Pembrolizumab (100 nM) and Nivolumab (100 nM), and CTLA-4 inhibitor Ipilimumab (100 nM). We found a limited effect of Pembrolizumab and Nivolumab. Anti-tumor cytotoxicity was markedly increased in combination of Imipramine blue with Pembrolizumab and R-propranolol with Nivolumab. We propose that these effects are mediated through the activation of the endogenous immune cells and/or via the regulation of the PD-L1 and NKD2 ligand expression levels in the melanoma cells to become more sensitized to immune cells. Further studies will aim to validate these results in immunoreactive organoids from both mice and human patients. Our studies will shed light on the immune and metabolic axes and the use of specific agonists to develop new immune therapy treatment strategies for melanoma. Citation Format: Azza M. El-derby, Nadeem Wajih, Jack Arbiser, Konstantinous Votanopoulos, Shay Soker. Manipulation of mitochondrial metabolism, through SIRT3 agonists, in a novel immunoreactive melanoma organoids model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6043.

Abstract 5865: Combinatorial activity of amivantamab and pembrolizumab in head and neck squamous cell carcinoma and lung squamous cell carcinoma expressing wild-type EGFR and MET

Abstract Introduction: Unmet needs exist for immunotherapy targeting PD-1/PD-L1 in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC) due to its suboptimal response. Amivantamab, a bispecific antibody targeting epidermal growth factor receptor (EGFR) and c-Met, has been demonstrated to induce antibody-dependent cytotoxicity and trogocytosis in tumor cells. We hypothesized that combination of amivantamab with pembrolizumab may synergistically enhance antitumor immunity. In this study, we present comprehensive immunomodulatory and synergistic antitumor efficacy of amivantamab and pembrolizumab in humanized HNSCC and LUSC mice models. Methods: EGFR and MET-expressing tumors from a HNSCC and a LUSC patient were transplanted into Hu-CD34-NSG to establish humanized patient-derived xenograft (PDX) models. Tumor-bearing PDXs were treated with vehicle, pembrolizumab (10mpk, Q5D, n=10), amivantamab (10mpk, BIW, n=10), or a combination of pembrolizumab and amivantamab (n=10). Analysis of immune modulatory responses within the tumor microenvironment (TME) using multiplexed IHC, flow cytometry, and single cell RNA sequencing was performed. Results: Combination of amivantamab and pembrolizumab showed a significant reduction of tumor volume (p<0.001) compared to vehicle or single treatment in both models. Additionally, significantly longer survival was observed for combination treated compared to the vehicle treated groups (p<0.0001). Multispectral imaging of tumor indicated that granzyme B-producing CD8+ T cells were significantly increased within the tumor in the combination group (p<0.01). Further analysis of T cell subsets suggested that central memory type CD8+ T cells were increased upon combination treatment. This group also demonstrated significantly higher CEA-tetramer positive CD8+ T cells in the tumor (p<0.01), suggesting that cytotoxic T cells recognizing tumor specific antigens enhanced antitumor immune response. Single cell RNA sequencing analysis of HNSCC showed that an EGFRhighMEThigh cluster was enriched in the TME after pembrolizumab treatment. This subcluster had elevated glycolysis and lactic acid pathway-related genes compared to EGFRlowMETlow cluster. Lactate transporter, MCT4 (SLC16A3) and LDHA genes were dramatically increased in the EGFRhighMEThigh cluster. Elevated lactic acid pathway may lead to immune evasion in the tumor, dampening the activity of pembrolizumab. Interestingly, combination treatment with amivantamab could reduce EGFRhighMEThigh cluster, and could effectively control tumor via creating favorable immune TME. Conclusion: Our study demonstrated combinatorial benefits of amivantamab and pembrolizumab by effectively remodeling TME, providing a preclinical rationale to clinically combine amivantamab and PD-1 blockade treatments. Citation Format: Sun Min Lim, Chun-Bong Synn, Seong-san Kang, DongKwon Kim, Soo-Hwan Lee, Sujeong Baek, Seung Min Yang, Yu Jin Han, Mi hyun Kim, Heekyung Han, Kwangmin Na, Young Taek Kim, Sungwoo Lee, Mi Ran Yun, Jae Hwan Kim, Youngseon Byeon, Young Seob Kim, Jii Bum Lee, Ji Yun Lee, Chang Gon Kim, Min Hee Hong, Kyoung-Ho Pyo, Joshua Curtin, Bharvin Patel, Isabelle Bergiers. Combinatorial activity of amivantamab and pembrolizumab in head and neck squamous cell carcinoma and lung squamous cell carcinoma expressing wild-type EGFR and MET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5865.

Therapeutic efficacy of plant-produced Nivolumab in transgenic C57BL/6-hPD-1 mouse implanted with MC38 colon cancer

The therapeutic blockade of inhibitory PD-1 signaling has emerged as an effective approach for cancer immunotherapy. Nivolumab (Opdivo®), a monoclonal antibody (mAb) targeting the PD-1 immune checkpoint, is approved for treatment of several cancer indications. It functions by blocking the PD-1-mediated T-cell inhibition thus reinstating anticancer immune responses. Tremendous advances in plant biotechnology offer an alternative and economical strategy to produce therapeutic mAbs for immune-based therapies. In this study, recombinant anti-PD-1 Nivolumab was produced in Nicotiana benthamiana and the plant-produced anti-PD-1 mAb was exploited for cancer treatment in syngeneic mice model C57BL/6 mice that were used to test the antitumor efficacy of plant produced Nivolumab, along with commercial Opdivo®. C57BL/6 syngeneic mice treated with plant produced anti-PD-1 mAb exhibited reduction in the growth of established MC38 tumors. The plant produced Nivolumab treatment showed 82.9% antitumor effect in decreasing the tumor volume along with 50% tumor-free mice, whereas Opdivo® showed 90.26% reduction in volume without any tumor-free mice. Finally, plant-derived anti-PD-1 therapy was also well tolerated in tumor-bearing mice that correlated with no significant body weight changes. Overall, our plant-produced Nivolumab elicits significant inhibition of tumor growth in vivo and provides a proof-of-concept for the production of immunotherapy targeting PD-1.

Immunotherapy Targeting PD-1/PD-L1 in Early-Stage Triple-Negative Breast Cancer.

The advent of immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized antitumor therapy. Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are among the most promising targets for encouraging the immune system to eliminate cancer cells. PD-1/PD-L1 have made clinical remission for numerous solid tumors, including metastatic triple-negative breast cancer (TNBC). In recent years, integrating PD-1/PD-L1 inhibitors into existing treatments in early-stage TNBC has attracted wide attention. Herein, we summarize the clinical benefit of PD-1/PD-L1 inhibitors plus neoadjuvant chemotherapy, adjuvant chemotherapy, and targeted therapy in early-stage TNBC. Possible immunotherapy biomarkers, immune-related adverse events (irAEs), and the key challenges faced in TNBC anti-PD-1/PD-L1 therapy are also concluded. Numerous studies on immunotherapy are ongoing, and PD-1/PD-L1 inhibitors have demonstrated great clinical prospects in early-stage TNBC. To maximize the efficacy of anti-PD-1/PD-L1 therapy, further research into the challenges which still exist is necessary.

Retrospective Analysis of the Predictive Value of 18F-FDG PET/CT Metabolic Parameters for PD-L1 Expression in Cervical Cancer

Immunotherapy targeting PD-1/PD-L1 has been proven to be effective for cervical cancer treatment. To explore non-invasive examinations for assessing the PD-L1 status in cervical cancer, we performed a retrospective study to investigate the predictive value of 18F-FDG PET/CT. The correlations between PD-L1 expression, clinicopathological characteristics and 18F-FDG PET/CT metabolic parameters were evaluated in 74 cervical cancer patients. The clinicopathological characteristics included age, histologic type, tumor differentiation, FIGO stage and tumor size. The metabolic parameters included maximum standard uptake (SUVmax), mean standard uptake (SUVmean), total lesion glycolysis (TLG) and tumor metabolic volume (MTV). In univariate analysis, SUVmax, SUVmean, TLG, tumor size and tumor differentiation were obviously associated with PD-L1 status. SUVmax (rs = 0.42) and SUVmean (rs = 0.40) were moderately positively correlated with the combined positive score (CPS) for PD-L1 in Spearman correlation analysis. The results of multivariable analysis showed that the higher SUVmax (odds ratio = 2.849) and the lower degree of differentiation (Odds Ratio = 0.168), the greater probability of being PD-L1 positive. The ROC curve analysis demonstrated that when the cut-off values of SUVmax, SUVmean and TLG were 10.45, 6.75 and 143.4, respectively, the highest accuracy for predicting PD-L1 expression was 77.0%, 71.6% and 62.2%, respectively. The comprehensive predictive ability of PD-L1 expression, assessed by combining SUVmax with tumor differentiation, showed that the PD-L1-negative rate was 100% in the low probability group, whereas the PD-L1-positive rate was 84.6% in the high probability group. In addition, we also found that the H-score of HIF-1α was moderately positively correlated with PD-L1 CPS (rs = 0.51). The SUVmax and differentiation of the primary lesion were the optimum predictors for PD-L1 expression in cervical cancer. There was a great potential for 18F-FDG PET/CT in predicting PD-L1 status and selecting cervical cancer candidates for PD1/PD-L1 immune checkpoint therapy.

IFN-γ Signaling Sensitizes Melanoma Cells to BH3 Mimetics

Immunotherapy targeting PD-1 and/or CTLA4 leads to durable responses in a proportion of patients with melanoma. However, many patients will not respond to these immune checkpoint inhibitors, and up to 60% of responding patients will develop treatment resistance. We describe a vulnerability in melanoma driven by immune cell activity that provides a pathway towards additional treatment options. This study evaluated short-term melanoma cell lines (referred to as PD1 PROG cells) derived from melanoma metastases that progressed on PD-1 inhibitor-based therapy. We show that the cytokine IFN-γ primes melanoma cells for apoptosis by promoting changes in the accumulation and interactions of apoptotic regulators MCL-1, NOXA, and BAK. The addition of pro-apoptotic BH3 mimetic drugs sensitized PD1 PROG melanoma cells to apoptosis in response to IFN-γ or autologous immune cell activation. These findings provide translatable strategies for combination therapies in melanoma.

A Novel TrxR1 Inhibitor Regulates NK and CD8+ T Cell Infiltration and Cytotoxicity, Enhancing the Efficacy of Anti-PD-1 Immunotherapy against Hepatocarcinoma.

Hepatocellular carcinoma (HCC) has the third highest cancer-related mortality rate globally. The immunosuppressive microenvironment of HCC limits effective treatment options. HCC cells and associated microenvironmental factors suppress NK and T cell infiltration and cytotoxic activities. The abnormal number or function of NK and T cells leads to a lack of immune surveillance. Recently, immunotherapy targeting PD-1 and PD-L1 has been shown to activate functionally exhausted cytotoxic immune cells in some solid tumors. However, the response rate and therapeutic efficacy against solid tumors with little lymphocyte infiltration are limited, especially for HCC. Therefore, new targets and therapeutics that induce tumor cell apoptosis and overcome the problem of depletion of immune cells, thereby inhibiting the immune escape of HCC cells, are urgently required. Butaselen (2-bis[2-(1,2-benzisothiazol-2(2H)-ketone)]butane), an organic molecule containing selenium, is a new type of thioredoxin reductase inhibitor. In this study, we found that butaselen promoted NK and T cell activity and infiltration in the tumor microenvironment in HCC-bearing mice by enhancing the expression of CXCR3, NKG2D, and their respective ligands. When used alone, it can significantly inhibit tumor growth and exert a synergistic effect in combination with PD-1 blockade. We suggested the role of the thioredoxin reductase system in the regulation of the tumor immunosuppressive microenvironment and developed a new effective therapeutic molecule for HCC, revealing the mechanism of butaselen in inhibiting tumor cell immune escape.

Correlation analysis of Poor Prognosis and Immunotherapy of lncRNAs Related with m 6A Modification in Cervical Cancer

To study the correlation between N 6-methyladenosine (m 6A)-modification-associated long non-coding RNAs (lncRNAs) and poor prognosis and immunotherapy in cervical cancer based on data mining of The Cancer Genome Atlas (TCGA) cervical cancer dataset, so as to assess effectively the prognosis of cervical cancer patients and the feasibility of immunotherapy. We identified m 6A-modification-associated lncRNAs correlated to the prognosis of cervical cancer by conducting bioinformatics analysis of cervical cancer samples from the TCGA datasets and constructed a prognostic risk model of cervical cancer accordingly. A total of 343 m 6A-modification-associated lncRNAs were identified from the samples of 304 cervical cancer patients. Univariate Cox regression analysis showed that 26 out of the 343 m 6A-modification-associated lncRNAs were significantly associated with the prognosis of cervical cancer patients. We identified 7 m 6A-modification-associated lncRNAs, including DLEU1, AC099850.4, DDN-AS1, EP300-AS1, AC131159.1, AL441992.2, and AL021707.6 through Lasso regression analysis and then developed a prognostic risk model based on them. According to the Kaplan-Meier survival analysis, cervical cancer patients in the low-risk group exhibited significantly improved overall survival (OS) in comparison with those in the high-risk group ( P<0.001). The area under the curve ( AUC) of receiver operating characteristic (ROC) curve analysis demonstrated the high sensitivity and credibility of the risk model. Multivariate Cox analysis showed that the risk score was an independent prognostic factor of cervical cancer patients. Tumor immune dysfunction and exclusion (TIDE) analysis predicted that the high-risk group would benefit more from immunotherapy. In addition, we found that immune checkpoint PD1 was associated with the expression of m6A-modification-related lncRNAs such as DDN-AS1, and the expression was higher in the high-risk group ( P<0.05). The prognostic risk model constructed on the basis of the aforementioned 7 m 6A-modification-associated lncRNAs can be used to effectively predict the prognosis of cervical cancer patients and assess the efficacy of immunotherapy targeting PD1.

A Prognostic Model for Colon Adenocarcinoma Patients Based on Ten Amino Acid Metabolism Related Genes

BackgroundAmino acid metabolism plays a vital role in cancer biology. However, the application of amino acid metabolism in the prognosis of colon adenocarcinoma (COAD) has not yet been explored. Here, we construct an amino acid metabolism-related risk model to predict the survival outcome of COAD and improve clinical decision making.MethodsThe RNA-sequencing-based transcriptome for 524 patients with COAD from The Cancer Genome Atlas (TCGA) was selected as a training set. The integrated Gene Expression Omnibus (GEO) dataset with 1,430 colon cancer samples was used for validation. Differential expression of amino acid metabolism-related genes (AAMRGs) was identified for prognostic gene selection. Univariate cox regression analysis, LASSO-penalized Cox regression analysis, and multivariate Cox regression analysis were applied to construct a prognostic risk model. Moreover, the correlation between risk score and microsatellite instability, immunotherapy response, and drug sensitivity were analyzed.ResultsA prognostic signature was constructed based on 10 AAMRGs, including ASPG, DUOX1, GAMT, GSR, MAT1A, MTAP, PSMD12, RIMKLB, RPL3L, and RPS17. Patients with COAD were divided into high-risk and low-risk group based on the medianrisk score. Univariate and multivariate Cox regression analysis revealed that AAMRG-related signature was an independent risk factor for COAD. Moreover, COAD patients in the low-risk group were more sensitive to immunotherapy targeting PD-1 and CTLA-4.ConclusionOur study constructed a prognostic signature based on 10 AAMRGs, which could be used to build a novel prognosis model and identify potential drug candidates for the treatment of COAD.

Endometrial Cancer Stem Cells: Where Do We Stand and Where Should We Go?

Endometrial cancer is one of the most common malignant diseases in women worldwide, with an incidence of 5.9%. Thus, it is the most frequent cancer of the female genital tract, with more than 34,000 women dying, in Europe and North America alone. Endometrial Cancer Stem Cells (CSC) might be drivers of carcinogenesis as well as metastatic and recurrent disease. Therefore, targeting CSCs is of high interest to improve prognosis of patients suffering of advanced or recurrent endometrial cancer. This review describes the current evidence of molecular mechanisms in endometrial CSCs with special emphasis on MYC and NF-κB signaling as well as mitochondrial metabolism. Furthermore, the current status of immunotherapy targeting PD-1 and PD-L1 in endometrial cancer cells and CSCs is elucidated. The outlined findings encourage novel therapies that target signaling pathways in endometrial CSCs as well as immunotherapy as a promising therapeutic approach in the treatment of endometrial cancer to impede cancer progression and prevent recurrence.

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors

BackgroundsIn advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.MethodsTumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry,...

Combination Cancer Immunotherapy Targeting TNFR2 and PD-1/PD-L1 Signaling Reduces Immunosuppressive Effects in the Microenvironment of Pancreatic Tumors

Combination Cancer Immunotherapy Targeting TNFR2 and PD-1/PD-L1 Signaling Reduces Immunosuppressive Effects in the Microenvironment of Pancreatic Tumors

Dl-3-N-Butylphthalide Presents Anti-Cancer Activity in Lung Cancer by Targeting PD-1/PD-L1 Signaling.

IntroductionLung cancer serves as one of the most malignant cancer types. Immunotherapy targeting PD-1/PD-L1 axis is a promising strategy for cancer treatment. Dl-3-N-butylphthalide (NBP), a small molecule compound extracted from the seeds of Apium graveolens, possesses a large range of biological effects and demonstrates anti-cancer activities. However, the role of NBP in the modulation of lung cancer remains obscure.MethodsIn this study, we aimed to explore the effect of NBP on PD-L1 signaling and the progression of lung cancer.ResultsSignificantly, the treatment of NBP repressed the proliferation of lung cancer cells in vitro. Tumorigenicity analysis in nude mice showed that the tumor volume and tumor weight were attenuated by the treatment of NBP in the mice. Meanwhile, the levels of Ki-67 and PD-L1 were reduced by the treatment of NBP in the tumor tissues of the mice. NBP suppressed IFN-γ-induced PD-L1 enhancement in lung cancer cells. The treatment of NBP inhibited PD-L1 expression in lung cancer cells co-cultured with unstimulated PBMCs or activated T cell. NBP inhibited PD-1 expression in activated T cells co-cultured with lung cancer cells. Conditioned medium from activated T cells increased PD-L1 expression, and NBP reversed this effect. Co-culture with A549 and H1975 cells reduced T cell proliferation and activity, while the treatment of NBP reversed the reduction. Consistently, the treatment of NBP caused notably decreased apoptosis of co-cultured T cells. Mechanically, KAT7 was able to bind to PD-L1 promoter and epigenetically induce PD-L1 expression by promoting the enrichment of histone H3 lysine 14 acetylation (H3K14ac) and RNA polymerase II on PD-L1 promoter.DiscussionThus, we concluded that NBP repressed PD-L1 expression by targeting KAT7 and attenuated PD-1/PD-L1 axis to relieve lung cancer progression. NBP may be applied as the potential therapeutic strategy in immunotherapy of lung cancer.