Treatment Of Multiple Cancers Research Articles

87P Infliximab use in patients with checkpoint inhibitor toxicities: A tertiary centre experience

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of multiple cancers. However, they are associated with a spectrum of immune-related adverse events (irAEs). Infliximab is a recommended treatment for corticosteroid refractory irAEs, but real-world data is limited.

Isothiocyanates attenuate immune checkpoint blockage therapy in gastric cancer via induction of PD-L1 expression

The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric cancer. Isothiocyanates play important roles in cancer cell suppression and immunomodulation. However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate, and benzhydryl isothiocyanate) on gastric cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody, and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation. Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric cancer cells to anti-PD-L1 drug. Moreover, in vivo studies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric cancer.

Oral Supramolecular Adsorbent for Preventing Chemo-Induced Gastrointestinal Mucositis and Microbial Dysbiosis and for Enhancing Chemoimmunotherapy.

The addition of immune checkpoint blockade (ICB) to cytotoxic chemotherapy has emerged as the first-line treatment for multiple cancers. Paradoxically, cytotoxic chemotherapy may limit the therapeutic potential of ICB by significantly impairing the largest immune organ, the gastrointestinal (GI) tract, and driving gut microbial dysbiosis. Here, an orally administered polymeric adsorbent containing a supramolecular motif (named SPORA-SN9) is reported, which can selectively remove chemotherapeutics from the GI tract, thereby preventing chemotherapy-induced GI mucositis and microbial dysbiosis and providing better chemoimmunotherapy synergy. By theoretical design and experimental screening of the molecular recognition motifs, SPORA-SN9 exhibits superior complexation capacity for doxorubicin and irinotecan and high selectivity over a range of commonly used combinational medications. In mouse models of chemotherapy-induced GI mucositis, SPORA-SN9 protects the integrity of the GI tissues and the homeostasis of the gut microbiota. Finally, the addition of SPORA-SN9 enhances the efficacy of chemoimmunotherapy in tumor-bearing mice. SPORA-SN9 offers a translational approach for supramolecular chemistry to modulate complex biosystems by selectively removing target substrates from the GI tract.

The novel BRDT inhibitor NHWD870 shows potential as a male contraceptive in mice.

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) family proteins have emerged as promising options not only for the treatment of multiple cancers but also for disturbing the process of sperm maturation with potential for use as viable contraceptive targets. In this study, we find that the BET family inhibitor NHWD870 and BRDT can bind well in vitro through bioinformatics software prediction and protein binding inhibition experiments. NHWD870 can produce a good contraceptive effect through animal experiments in vivo, and the fertility can be restored to normal after drug withdrawal. Transcriptomics and proteomics results suggest that NHWD870 affects pathways related to spermatogenesis and maturation, further contributing to the male infertility phenotype. Our results show that NHWD870 can induce a complete and reversible contraceptive effect in mice, which is stronger than that of JQ1 and its synthesized derivatives. This study is expected to eventually lead to clinical trials.

COVID-19 vaccination perception and uptake among cancer patients in Guangzhou, China

ABSTRACT Patients with cancer are considered at high risk of COVID-19 related complications with higher mortality rates than healthy individuals. This study investigated the perception, acceptance, and influencing factors of COVID-19 vaccination among cancer patients in Guangzhou, China. A cross-sectional survey was conducted in Guangzhou, China from August to November 2021 in two tertiary medical centers. Outpatients were recruited through hospital posters to complete a questionnaire including demographics, medical history, knowledge, and attitude toward COVID-19 vaccines and COVID-19 vaccination status. Chi-square tests and multivariable logistic regression were used to analyze predictors for acceptance of COVID-19 vaccination. In total, only 75 out of 343 patients (21.87%) had received at least one dose of COVID-19 vaccine. Twenty-one patients (6.12%) had received a recommendation about COVID-19 vaccination from their physicians. Patients who were recommended by physicians to get vaccinated (aOR = 11.71 95% CI: 2.71–50.66), with a monthly income of more than CNY 5000 (aOR = 3.94, 95% CI: 1.88–8.26) were more likely to have received COVID-19 vaccination. Cancer patients who had been diagnosed for more than one year (aOR = 0.21, 95% CI: 0.09–0.51), had received multiple cancer treatment strategies (aOR = 0.34, 95% CI: 0.16–0.74), worried about the safety of COVID-19 vaccines (aOR = 0.21, 95% CI: 0.11–0.40), were less likely to have received COVID-19 vaccination. COVID-19 vaccination uptake among cancer patients was insufficient. The proportion of cancer patients receiving vaccination recommendations from physicians remains inadequate. Physicians are expected to play an essential role in patients’ knowledge of the safety and effectiveness of COVID-19 vaccines.

Abstract 5463: BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers

Abstract Src homology region 2 domain-containing phosphatase-2 (SHP-2) is a key node in the RAS signaling pathway. Allosteric inhibition of SHP2 phosphatase is a potential therapeutic strategy for cancers harboring oncogenic mutations in the KRAS pathway. SHP2 also participates in the signal transduction downstream of regulatory immunoreceptors, and it has been shown in preclinical models that SHP2 inhibition drives anti-tumor immunity through modulation of both innate and adaptive mechanism. BPI-442096 is a potent, selective, and orally bioavailable small molecule SHP2 inhibitor. It exhibited significant anti-proliferation activities against multiple KRAS mutant cancer cell lines, including those from NSCLC, PDAC, CRPC, etc. BPI-442096 dose-dependently inhibited SHP2 phosphatase and downstream ERK phosphorylation in cancer cells, as well as NFAT reporter gene expression downstream of PD-1/PD-L1 signaling in immune cells. In vivo, BPI-442096 demonstrated strong tumor growth inhibition in KRASG12C, KRASG12D, and KRASG12V mutant xenograft mouse models. BPI-442096 also exhibited anti-tumor immunity in the MC38 syngeneic model, as a single agent or in combination with anti-PD1/PD-L1 drugs. Moreover, BPI-442096 combining with KRASG12C inhibitor may reverse intrinsic and acquired resistance to KRASG12C inhibition. Adequate oral exposure across multiple pre-clinical species and good ADME properties ensured the druggability of BPI-442096. In conclusion, BPI-442096 exhibits a robust anti-tumor effect in multiple KRAS mutant models and enhanced anti-cancer immunity in syngeneic mouse models, and it shows multiple combination potentials to overcome drug resistance. Phase 1 clinical trial is planned in early 2022. Citation Format: Ling Li, Bang Fu, Han Han, Zhongxin Sun, Xiangdong Zhao, Xuepeng Jv, Jun Tong, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Wei Ren, Yinlong Li, Wenmao Wu, Jing Guo, Dan Yan, Xiangyong Liu, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5463.

FOXA1 Leads to Aberrant Expression of SIX4 Affecting Cervical Cancer Cell Growth and Chemoresistance.

Cervical cancer (CC) is among the most prevalent cancers among female populations with high recurrence rates all over the world. Cisplatin (DDP) is the first-line treatment for multiple cancers, including CC. The main problem associated with its clinical application is drug resistance. This study is aimed at investigating the function and downstream regulation mechanism of forkhead-box A1 (FOXA1) in CC, which was verified as an oncogene in several cancers. Using GEO database and bioinformatics analysis, we identified FOXA1 as a possible oncogene in CC. Silencing of FOXA1 inhibited CC cell growth, invasion, and chemoresistance. Afterwards, the downstream gene of FOXA1 was predicted using a bioinformatics website and validated using ChIP and dual-luciferase assays. SIX4, a possible target of FOXA1, promoted CC cell malignant aggressiveness and chemoresistance. In addition, overexpression of SIX4 promoted phosphorylation of PI3K and AKT proteins and activated the PI3K/AKT signaling pathway. Further overexpression of SIX4 reversed the repressive effects of FOXA1 knockdown on CC cell growth, invasion, and chemoresistance in DDP-resistant cells. FOXA1-induced SIX4 facilitates CC progression and chemoresistance, highlighting a strong potential for FOXA1 to serve as a promising therapeutic target in CC.

Genome-wide survey of the GATA gene family in camptothecin-producing plant Ophiorrhiza pumila

BackgroundOphiorrhiza pumila (Rubiaceae) is capable of producing camptothecin (CPT), one monoterpene indole alkaloid extensively employed in the treatment of multiple cancers. Transcription factors (TFs) GATA are a group of transcription regulators involved in plant development and metabolism, and show the feature of binding to the GATA motif within the promoters of target genes. However, GATA TFs have not been characterized in O. pumila.ResultIn this study, a total of 18 GATA genes classified into four subfamilies were identified, which randomly distributed on 11 chromosomes of O. pumila. Synteny analysis of GATA genes between O. pumila and other plant species such as Arabidopsis thaliana, Oryza sativa, Glycine max, Solanum lycopersicum, Vitis vinifera, and Catharanthus roseus genomes were analyzed. Tissue expression pattern revealed that OpGATA1 and OpGATA18 were found to be correlated with ASA, MK, CPR and GPPS, which were highly expressed in leaves. OpGATA7, showed high expression in roots as most of the CPT biosynthetic pathway genes did, suggesting that these OpGATAs may be potential candidates regulating CPT biosynthesis in O. pumila.ConclusionsIn this study, we systematically analyzed the OpGATA TFs, and provided insights into the involvement of OpGATA TFs from O. pumila in CPT biosynthesis.

Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases.

CARM1 (coactivator-associated arginine methyltransferase 1), which belongs to type I PRMTs (protein arginine methyltransferases), is a potential therapeutic target for treatment of multiple cancers. In this study, we first identified several hit compounds against CARM1 by structure-based virtual screening (IC50 = 35.51 ± 6.68 to 68.70 ± 8.12 μM) and then carried out chemical structural optimizations, leading to six compounds with significantly improved activities targeting CARM1 (IC50 = 18 ± 2 to 107 ± 6 nM). As a compound with an ethylenediamino motif, the most potent inhibitor, ZL-28-6, also exhibited potent inhibition against other type I PRMTs. Compared to the type I PRMT inhibitor from our previous work (DCPR049_12), ZL-28-6 showed increased potency against CARM1 and decreased activity against other type I PRMTs. Moreover, ZL-28-6 showed better antiproliferation activities toward a series of solid tumor cells than DCPR049_12, indicating its broad spectrum of anticancer activity. In addition, cellular thermal shift and Western blot assays validated that ZL-28-6 could target CARM1 in cells. Taken together, the inhibitor we identified could serve as a potent probe for studying CARM1's biological functions and shed light on the future design of novel CARM1 inhibitors with stronger activities and selectivities.

Combinatorial Therapeutic Approaches with Nanomaterial-Based Photodynamic Cancer Therapy.

Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies.

TRPV1 is a potential biomarker for the prediction and treatment of multiple cancers based on a pan-cancer analysis.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) was considered to play pivotal roles in multiple cancers; however, the expression and clinical significance of the TRPV1 remain unclear, which were explored in this study. The pan-cancer analysis was performed based on 10,236 samples in 32 cancers. Differential TRPV1 expression levels were detected in 12 cancers (p < 0.05). TRPV1 demonstrated its conspicuous prognosis significance and prediction effects for some cancers (e.g., lung adenocarcinoma), indicating its potential as a valuable and novel biomarker in treating and predicting cancers. TRPV1 expression was relevant to DNA methyltransferases, mismatch repair genes, tumor mutational burden, and microsatellite instability. TRPV1 expression was associated with the immune microenvironment of some cancers, and its roles in different cancers may be mediated by affecting various immune cells. Gene set enrichment analysis discloses the significant relevance of TRPV1 expression with a series of metabolic and immunoregulatory-related pathways. This study provided a comprehensive workflow of the expression, clinical significance, and underlying mechanisms of TRPV1 in pan-cancer. TRPV1 may be an underlying biomarker for predicting and treating multiple cancer.

ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma.

Resistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against gemcitabine chemotherapy. Recently, we showed the add-on effect of autophagy inhibitor UAMC-2526 to prevent HT-29 colorectal tumor growth in CD1-/- Foxn1nu mice treated with oxaliplatin. In this study, we aimed to investigate the potential beneficial effects of UAMC-2526 in a syngeneic Panc02 mouse model of pancreatic ductal adenocarcinoma (PDAC). Our data showed that UAMC-2526 combined with gemcitabine significantly reduced tumor growth as compared to the individual treatments. However, in contrast to in vitro experiments with Panc02 cells in culture, we were unable to detect autophagy inhibition by UAMC-2526 in Panc02 tumor tissue, neither via western blot analysis of autophagy markers LC3 and p62, nor by transmission electron microscopy. In vitro experiments revealed that UAMC-2526 enhances the potential of gemcitabine to inhibit Panc02 cell proliferation without obvious induction of cell death. Altogether, we conclude that although the combination treatment of UAMC-2526 with gemcitabine did not inhibit autophagy in the Panc02 mouse model, it has a beneficial effect on tumor growth inhibition.

Rheumatic Manifestations and Diseases From Immune Checkpoint Inhibitors in Cancer Immunotherapy.

Immune checkpoint inhibitors (ICIs), which can enhance antitumor immunity and inhibit cancer growth, have revolutionized the treatment of multiple cancers and dramatically decreased mortality. However, treatment with ICIs is directly associated with immune-related adverse events (irAEs) because of inflammation in off-target organs and autoimmunity resulting from non-specific immune activation. These irAEs can cause rheumatic diseases and manifestations such as inflammatory arthritis, polymyalgia rheumatica, myositis, vasculitis, Sicca and Sjogen's syndrome, and systemic lupus erythematosus. Early diagnosis and treatment of these adverse events will improve outcomes and quality of life for cancer patients. The treatment of rheumatic diseases induced by ICIs requires multidisciplinary cooperation among physicians. Furthermore, the underlying mechanisms are not fully understood and it is difficult to predict and evaluate these side effects precisely. In this review, we summarize available studies and findings about rheumatic irAEs, focusing mainly on the clinical manifestations, epidemiology, possible mechanisms, and guiding principles for treating these irAEs.

The Significance of PARP1 as a biomarker for Predicting the Response to PD-L1 Blockade in Patients with PBRM1-mutated Clear Cell Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs) have become key agents in the management of clear cell renal cell carcinoma (ccRCC), but their benefits are limited and responders remain unidentified. We investigated the significance of PARP1 in ccRCC using RNA sequencing data for 311 tumors from patients enrolled in prospective clinical trials of PD-1 blockade. Among patients treated with nivolumab (n = 181), overall survival (OS) was significantly higher in the PARP1-low group than in the PARP1-high group (p = 0.006), and PARP1 status was significantly associated with OS (hazard ratio [HR] 1.7; p = 0.007). By contrast, for patients treated with everolimus (n = 130) there was no significant difference by PARP1 status for progression-free survival (PFS; p = 0.9) or OS (p = 0.38). In subgroup analysis for PBRM1-mutated ccRCC, PFS (p = 0.016) and OS (p = 0.004) were significantly longer in the group with PARP1-low status and PBRM1 mutation in comparison to the other groups. In addition, PARP1 status was significantly associated with PFS (HR 2.6; p = 0.007) and OS (HR 3.5; p = 0.016) among patients with PBRM1-mutated ccRCC treated with nivolumab. Our study suggests that PARP1 can be used as a biomarker for predicting response to ICI treatment for patients with PBRM1-mutated ccRCC. Patient summaryImmune checkpoint inhibitors (ICIs) are key agents in the treatment of multiple cancers. We found that expression of the PARP1 protein was associated with survival after ICI treatment and with the response to ICI treatment in patients with clear cell kidney cancer who have a mutation of the PBRM1 gene.

Quercetin inhibiting the PD-1/PD-L1 interaction for immune-enhancing cancer chemopreventive agent.

Targeting the PD-1/PD-L1 immune checkpoints has achieved significant positive results in the treatment of multiple cancers. Quercetin is one of the most abundant dietary flavonoids found in various vegetables and fruits, and has a wide range of biological activities including immunomodulation. Here we report that quercetin dihydrate was screened and shown to inhibit the PD-1/PD-L1 interaction. Treatment with quercetin dihydrate promoted the killing activity of T cells on MDA-MB-231 and NCI-H460 cancer cells. Experiments using the xenograft mouse model showed that the growth rate of tumor volumes and masses in the quercetin dihydrate-treated mice were decreased. Immunohistochemistry of the tumors showed that CD8, GZMB, and IFN-γ were increased in the quercetin dihydrate-treated mice. These results suggest that quercetin dihydrate attenuates the inhibitory effect of PD-L1 on T cells by inhibiting the PD-1/PD-L1 interaction, which has an exciting potential to be used as a cancer chemopreventive agent.

Ferroptosis-related lncRNA pairs to predict the clinical outcome and molecular characteristics of pancreatic ductal adenocarcinoma.

Ferroptosis is a form of regulated cell death initiated by oxidative perturbations that can be blocked by iron chelators and lipophilic antioxidants, and ferroptosis may be the silver bullet treatment for multiple cancers, including immunotherapy- and chemotherapy-insensitive cancers such as pancreatic ductal adenocarcinoma (PDAC). Numerous studies have noted that long non-coding RNAs (lncRNAs) regulate the biological behaviour of cancer cells by binding to DNA, RNA and protein. However, few studies have reported the role of lncRNAs in ferroptosis processes and the function of ferroptosis-associated lncRNAs. The primary objective of the present study was to identify ferroptosis-related lncRNAs using bioinformatic approaches combined with experimental validation. The second objective was to construct a prognostic model to predict the overall survival of patients with PDAC. The present study identified ferroptosis-related lncRNAs using a bioinformatic approach and validated them in an independent pancreatic cancer cohort from Fudan University Shanghai Cancer Center. The lncRNA SLCO4A1-AS1 was identified as a novel molecule mediating ferroptosis resistance in vitro. A novel algorithm was used to construct a '0 or 1' matrix-based prognosis model, which showed promising diagnostic accuracy for potential clinical translation (area under the curve = 0.89 for the 2-year survival rate). Notably, molecular subtypes classified by the risk scores of the model did not belong to any previously reported subtypes of PDAC. The immune microenvironment, metabolic activities, mutation landscape and ferroptosis sensitivity were significantly distinct between patients with different risk scores. Sensitivity (IC50) to 30 common anticancer drugs was analysed between patients with different risks, and imatinib and axitinib were found to be potential drugs for the treatment of patients with lower risk scores. Overall, we developed an accurate prognostic model based on the expression patterns of ferroptosis lncRNAs, which may contribute greatly to the evaluation of patient prognosis, molecular characteristics and treatment modalities and could be further translated into clinical applications.

The Experiences of Chinese Children 5- to 7-year-old during Cancer Treatment Reflected Through Interviews and Drawings.

Background: For children with cancer, the experience during treatment can be challenging. There is a limited number of studies on self-reported treatment experiences of younger Chinese children with cancer using qualitative methods. Objectives: This study aimed at exploring the experience of Chinese children aged 5 to 7 years during cancer treatment reflected through interviews and drawings. Methods: This study used a descriptive qualitative design with the technique of "draw-and-tell." Participants were enrolled from the pediatric oncology inpatient department of one national children's medical center in China. They were asked to draw a picture of "your feelings in the hospital." An inductive content analysis approach was used. Results: Twelve participants were enrolled (8 male, mean age 5.7 years). Four themes were established: (1) suffering from adverse treatment effects; (2) perceiving changed relationships; (3) being thankful for others; and (4) trying out coping strategies. Conclusion: Chinese children aged 5 to 7 years expressed multiple cancer treatment impacts. They appreciated others' support and had their own way to cope with treatment demands. The authors also extended the dynamic nature of using the "draw-and-tell" methodology. Study findings highlight the importance of inviting and hearing the voice of young children during their cancer treatment, with particular consideration of the influence of disease, treatment, child development, family dynamics, and culture.

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow.

Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

Tyrosine Kinase Inhibitors Stimulate HLA Class I Expression by Augmenting the IFNγ/STAT1 Signaling in Hepatocellular Carcinoma Cells.

Combination treatment with tyrosine kinase inhibitors (TKIs) and immunotherapies has shown efficacy in the treatment of multiple cancers, but the immunomodulatory effect of TKIs on the tumor cell phenotype remains unknown in hepatocellular carcinoma (HCC). Given that human lymphocyte antigen class I (HLA-I) is essential for tumor antigen presentation and subsequent antitumor immunity, we examined the effects of regorafenib, as well as other TKIs (sorafenib, lenvatinib and cabozantinib) on HLA-I expression in HCC cell lines. Regorafenib increased cell surface HLA-I and β2-microglobulin protein expression in the presence of interferon γ (IFNγ). The expressions of various genes associated with the HLA-I antigen processing pathway and its transcriptional regulators were also upregulated by regorafenib. Furthermore, we found that regorafenib had an activating effect on signal transducers and activators of transcription 1 (STAT1), and that regorafenib-induced HLA-I expression was dependent on the augmented IFNγ/STAT1 signaling pathway. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also activated IFNγ/STAT1 signaling and increased HLA-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not. Given that regorafenib directly inhibits Raf/MEK/ERK signaling, the downregulation of the MEK/ERK pathway appears to be one of the mechanisms by which regorafenib promotes STAT1 activation. Sorafenib, lenvatinib, and cabozantinib also showed the same effects as regorafenib, while regorafenib had most potent effects on HLA-I expression, possibly dependent on its stronger inhibitory activity against the MEK/ERK pathway. These results support the clinical combination of TKIs with immunotherapy for the treatment of HCC.

28452 A case of ecthyma in patients with bevacizumab

Ecthyma is an ulcerative pyoderma of the skin, well known to be caused by S aureus and/or group A Streptococcus. Bevacizumab is an IgG1 humanized monoclonal antibody that neutralizes the effect of vascular endothelial growth factor (VEGF), which is for use in the treatment of multiple cancer. However, in bevacizumab, by inhibiting the pathway of VEGF that can interfere wound repair, and several cases have been reported of delayed wound healing in postoperative patients with bevacizumab. In our case, it is highly possible that bevacizumab disrupted wound healing process, and that ecthyma was caused by a secondary infection at the injection site.