Enhancement Of Antitumor Effect Research Articles

A Synergistic Combination of Oleanolic Acid and Apatinib to Enhance Antitumor Effect on Liver Cancer Cells and Protect against Hepatic Injury.

As a pentacyclic triterpenoid, OA (oleanolic acid) has exhibited antiinflammatory, immunomodulatory and antitumor effects. VEGFR-2 (vascular endothelial cells receptor-2) tyrosine kinase activity could be inhibited by apatinib, a small-molecule antiangiogenic agent. Thus, this study sought to investigate the mechanism underlying the synergistic antitumor activity of combined OA and apatinib patent. Through CCK8 (Cell counting kit 8 assay), flow cytometric and western blotting techniques, we conducted in vitro studies on apatinib and OA effects on cell proliferation and apoptosis in H22 cell line. H22 tumor-burdened mice model was established in vivo, while the related signaling pathways were studied via pathological examination, western blotting and qPCR (quantitative polymerase chain reaction). Growth of H22 cells in vitro and in vivo could be inhibited effectively by apatinib and OA. Thus, OA repaired liver function and inhibited oxidative stress induced by apatinib. OA can treat apatinib induced liver injury in H22 Tumor-burdened mice by enhancing the suppresssive effect of apatinib on the growth of tumor.

Nanoparticles with Active Targeting Ability and Acid Responsiveness for an Enhanced Antitumor Effect of Docetaxel.

Docetaxel (DOC) is commonly used in cancer treatment, especially for breast cancer. However, there are severe side effects in clinical application. In order to deliver docetaxel more effectively, a novel, active targeting acid-responsive polymer called cRGD-PAE-PEG-DSPE was developed. The polymer structure incorporated poly(ethylene glycol) (PEG) as the hydrophilic segment, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as the hydrophobic segment, and poly(β-amino ester) (PAE) as the acid-responsive group, which was grafted onto the PEG. Furthermore, c(RGDyC) was grafted onto PAE to confer active targeting capability. Through self-assembly, docetaxel was encapsulated in RAED@DOC. Through in vitro experiments, it was confirmed that RAED@DOC had good serum stability and acid responsiveness, as well as enhanced uptake by MDA-MB-231 cells. Additionally, the antitumor efficiency in vivo and histopathological analysis showed that RAED@DOC exhibited higher antitumor activity and lower systemic toxicity in comparison to free docetaxel. These results suggested that RAED@DOC had considerable potential clinical use.

Induction of ferroptosis by photodynamic therapy and enhancement of antitumor effect with ferroptosis inducers.

Photodynamic therapy (PDT) is an effective tumor treatment that involves the administration of a photosensitizer to generate cytotoxic 1O2 [reactive oxygen species (ROS)] from molecular oxygen that is produced from energy absorption following tumor irradiation at specific wavelengths. Ferroptosis is induced by the disruption of the glutathione peroxidase 4 (GPX4) antioxidant system, leading to lipid peroxidation. We hypothesized that talaporfin sodium-photodynamic therapy (TS-PDT)-generated ROS would lead to ferroptosis via accumulation of lipid peroxidation. Cell viability assay in TS-PDT-treated cells in combination with a ferroptosis inhibitor (ferrostatin-1: Fer-1) or ferroptosis inducers (imidazole ketone erastin: IKE, Ras-selective lethal 3: RSL3) was performed. Accumulation of lipid peroxidation, GPX4 antioxidant system and cystine/glutamate antiporter (system xc-) activity in TS-PDT-treated cells was investigated. In xenograft mice, the antitumor effect of TS-PDT in combination with ferroptosis inducers (IKE or sorafenib) was examined. TS-PDT-induced cell death was partly suppressed by Fer-1 and accompanied by lipid peroxidation. TS-PDT combined with IKE or RSL3 enhanced the induction of cell death. TS-PDT inhibited cystine uptake activity via system xc-. In vivo, the combination of TS-PDT and ferroptosis inducers (IKE or sorafenib) reduced tumor volume. This study found that the mechanism underlying TS-PDT-induced ferroptosis constitutes direct lipid peroxidation by the generated ROS, and the inhibition of system xc-, and that the combination of a ferroptosis inducer with TS-PDT enhances the antitumor effect of TS-PDT. Our findings suggest that ferroptosis-inducing therapies combined with PDT may benefit cancer patients.

Enhanced Antitumor Effect of the Combination of Bacille Calmette-Guérin and an Immune Checkpoint Inhibitor in Bladder Cancer-On-a-Chip

Enhanced Antitumor Effect of the Combination of Bacille Calmette-Guérin and an Immune Checkpoint Inhibitor in Bladder Cancer-On-a-Chip

Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?

Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER-targeting therapy benefits from the autophagy-enhancing strategy more than the autophagy-inhibiting strategy for antitumor and antimetastasis treatment.

MiR-466 Contributes to the Enhanced Antitumor Effect of Bortezomib on Non-Small-Cell Lung Cancer by Inhibiting CCND1

Introduction: Changes in microRNAs (miRs) contribute to the alternative chemo-resistance of cancers. Bortezomib (BTZ) is a well-characterized anticancer agent that inhibits proteasome, and its effect is associated with the function of miRs. Based on the data of microarray assay and comprehensive bioinformatics analyses, in the current study, we explored the role of miR-466 and its downstream effector CCND1 in the BTZ-resistance of non-small-cell lung cancer (NSCLC) cells. Methods: miR expression profiles in NSCLC tissues and paratumor tissues were determined with microarray assay. The potential miR involved in the chemo-resistance of NSCLC cells was explored via a series of bioinformatics analyses, and miR-466 was selected. Afterward, levels of miR-466 and CCND1 were investigated in NSCLC samples and analyzed by clinicopathologic parameters, including age, sex, stage of NSCLC, tumor size, tumor differentiation status, and lymphocytic infiltration status. The expression of CCND1 and miR-466 was then modulated in vitro to explore the influence on cell phenotypes, which was then verified with mouse models. Results: Based on microarray detection, 287 miRs were dysexpressed between NSCLC tissues and paratumor tissues, including 90 upregulated members and 197 downregulated members. After bioinformatics analyses and reverse transcription quantitative PCR validation, miR-466 and CCND1 were selected. Following clinical investigations, miR-466 was downregulated, while CCND1 was upregulated in NSCLC samples, contributing to the advanced cancer progression. The overexpression of CCND1 increased cell viability, suppressed cell apoptosis, decreased p21 and induced N-cadherin, CCND2, and CDK4 under BTZ treatment. The induced expression of miR-466 re-sensitized NSCLC cells to BTZ treatment. In the animal model, the overexpression of CCND1 impaired the inhibitory effect of BTZ on the growth and metastasis of solid tumor, which was restored by miR-466 induction. Conclusion: The findings showed that the interaction between BTZ, miR-466, and CCND1 determined the antitumor effect of BTZ on NSCLC.

Fabrication of Fucoxanthin/2-Hydroxypropyl-β-Cyclodextrin Inclusion Complex Assisted by Ultrasound Procedure to Enhance Aqueous Solubility, Stability and Antitumor Effect of Fucoxanthin

Fabrication of Fucoxanthin/2-Hydroxypropyl-β-Cyclodextrin Inclusion Complex Assisted by Ultrasound Procedure to Enhance Aqueous Solubility, Stability and Antitumor Effect of Fucoxanthin

Cyclic RGD-Decorated Liposomal Gossypol AT-101 Targeting for Enhanced Antitumor Effect.

Introduction(-)-Gossypol (AT-101), the (-)-enantiomer of the natural compound gossypol, has shown significant inhibitory effects on various types of cancers such as osteosarcoma, myeloma, glioma, lung cancer, and prostate cancer. However, the clinical application of (-)-gossypol was often hindered by its evident side effects and the low bioavailability via oral administration, which necessitated the development of suitable (-)-gossypol preparations to settle the problems. In this study, injectable cyclic RGD (cRGD)-decorated liposome (cRGD-LP) was prepared for tumor-targeted delivery of (-)-gossypol.MethodsThe cRGD-LP was prepared based on cRGD-modified lipids. For comparison, a non-cRGD-containing liposome (LP) with a similar chemical composition to cRGD-LP was specially designed. The physicochemical properties of (-)-gossypol-loaded cRGD-LP (Gos/cRGD-LP) were investigated in terms of the drug loading efficiency, particle size, morphology, drug release, and so on. The inhibitory effect of Gos/cRGD-LP on the proliferation of tumor cells in vitro was evaluated using different cell lines. The biodistribution of cRGD-LP in vivo was investigated via the near-infrared (NIR) fluorescence imaging technique. The antitumor effect of Gos/cRGD-LP in vivo was evaluated in PC-3 tumor-bearing nude mice.ResultsGos/cRGD-LP had an average particle size of about 62 nm with a narrow size distribution, drug loading efficiency of over 90%, and sustained drug release for over 96 h. The results of NIR fluorescence imaging demonstrated the enhanced tumor targeting of cRGD-LP in vivo. Moreover, Gos/cRGD-LP showed a significantly enhanced inhibitory effect on PC-3 tumors in mice, with a tumor inhibition rate of over 74% and good biocompatibility.ConclusionThe incorporation of cRGD could significantly enhance the tumor-targeting effect of the liposomes and improve the antitumor effect of the liposomal (-)-gossypol in vivo, which indicated the potential of Gos/cRGD-LP that warrants further investigation for clinical applications of this single-isomer drug.

Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Enhancement of anti-tumor effects of PD-1 inhibitors by modulation of lipid metabolism in tumor microenvironment

Enhancement of anti-tumor effects of PD-1 inhibitors by modulation of lipid metabolism in tumor microenvironment

Enhanced Antitumor Effect of Trastuzumab and Duligotuzumab or Ipatasertib Combination in HER-2 Positive Gastric Cancer Cells.

Simple SummaryThe ToGA trial has demonstrated, in HER2-expressing patients, that unresectable and advanced gastric cancer, chemotherapy and trastuzumab in combination increase overall survival, even if it is still unclear why after one year the same patients are non-responsive to trastuzumab treatment. Here, we have demonstrated that in HER2-positive gastric cancer cell lines, the addition of duligotuzumab, targeting HER3 receptor, or ipatasertib, targeting AKT protein, enhances the antitumor effect of trastuzumab in vitro through a full inhibition of the membrane signals, on HER2 and HER3, and of downstream signaling, including AKT, and MAPK pathways. Hence, this study suggests a novel and biomarker-driven therapeutic strategy supporting further evaluation of the anti-tumor efficacy of these combinations in HER2 human gastric cancer patients.The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by concomitant use with trastuzumab in vitro and are under clinical investigation. The aim of this study was to assess the antitumor activity of duligotuzumab, an anti HER3/EGFR antibody or ipatasertib, an AKT inhibitor, combined with trastuzumab in a panel of HER2-positive human gastric cancer cells (GCC), and the efficacy of such combinations in HER2-resistant cells. We have assessed the efficacy of duligotuzumab or ipatasertib and trastuzumab in combination, analyzing proliferation, migration and apoptosis and downstream intracellular signaling in vitro on human HER2-positive GCC (NCI-N87, OE33, OE19) and in negative HER2 GCC (MKN28). We observed a reduction of proliferation, migration and apoptotic rate in HER2-positive OE33, OE19 and N87 cell lines with the combination of duligotuzumab or ipatasertib plus trastuzumab. In particular, in OE33 and OE19 cell lines, the same combined treatment inhibited the activation of proteins downstream of HER2, HER3, AKT and MAPK pathways. Targeting both HER2 and HER3, or HER2 and AKT, results in an improved antitumor effect on HER2-positive GCC.

Combination of Disulfiram and Copper-Cysteamine Nanoparticles for an Enhanced Antitumor Effect on Esophageal Cancer.

Esophageal cancer (EC) is the sixth leading cause of cancer deaths worldwide with a low 5-year survival rate. More effective chemotherapeutic drugs, either new or repurposing ones, are urgently needed. Disulfiram (DSF) is a safe and public domain drug for alcohol addiction treatment and later shown to have anti-cancer capability, especially when administrated together with copper. The present study is to test the hypothesis that a newly developed copper-cysteamine (Cu-Cy) nanoparticles (NPs) can enhance the anti-tumor effect of DSF on esophageal cancer with reduced risk of copper poisoning. Our results showed that Cu-Cy NPs could greatly facilitate DSF to inhibit cell proliferation in cultured human esophageal cancer cells. Interestingly, the combined inhibitory function could be further enhanced when DSF and Cu-Cy NPs were present at an optimal molar ratio of 1:4. The results of the change in physical color, UV-vis absorption and fluorescence spectra, X-ray diffraction patterns, and FTIR spectra from a mixture of DSF and Cu-Cy NPs suggest a possible reaction between DSF and Cu-Cy NPs and the formation of new materials. Furthermore, cellular mechanistic studies revealed that the combination of DSF and Cu-Cy NPs resulted in reactive oxygen species (ROS) accumulation, and blocked nuclear translocation of NF-ƙB (p65) in esophageal cancer cells. Moreover, in xenograft nude mice, combined administration of DSF and Cu-Cy NPs greatly inhibited tumor growth without noticeable histological toxicity, while any single agent at the same doses presented no inhibitory function. Together, this study demonstrates an effective anti-cancer function of combined treatment of DSF and Cu-Cy NPs in vitro and in vivo, which could be a promising new chemotherapy for esophageal cancer patients.

Apigenin Enhanced Antitumor Effect of Cisplatin in Lung Cancer via Inhibition of Cancer Stem Cells

Cancer stem cell theory has been proposed to explain tumor heterogeneity and the carcinogenesis process. Highly tumorigenic lung cancer stem cells develop resistance to cisplatin (CDDP), a common chemotherapy drug. Herein, we attempted to clarify whether apigenin (API) can improve the antitumor efficiency of CDDP in lung cancer using cancer stem cells. Lung cancer stem cells were identified as CD 133 positive cancer cells in non-small cell lung cancer (NSCLC) A549, H1299 cells and CDDP-resistant NSCLC A549R cells. The cytotoxic effect of API was measured in CDDP-treated A549, H1299, and A549R cells. API repressed CD 133 positive cells and enhanced the antitumor effect of CDDP in A549, H1299, and A549R cells. The synergistic antitumor effect of API and CDDP was blocked by addition of the p53 inhibitor Pifithrin-α, and siRNA targeting the p53 gene in A549R cells. Furthermore, API eliminates CDDP-induced CSC via p53, since A549R cells lacking p53 and Pifithrin-α addition derepressed the decrease in CD 133 positive cells after API treatment in CDDP-treated A549 and A549R cells. The findings indicate that API might eliminate cancer stem cells and enhance the antitumor effects of CDDP in NSCLC via p53.

From Nanofibers to Nanorods: Nanostructure of Peptide‐Drug Conjugates Regulated by Polypeptide‐PEG Derivative and Enhanced Antitumor Effect

Adv. Funct. Mater. 2019, 29, 1806058 The initially published version of this article contained a typographical error in the affiliation linked with the author Gang Cao (Zhengjiang Chinese Medical University). The correct affiliation details are as follows: Prof. G. Cao School of Pharmacy Zhejiang Chinese Medical University Hangzhou 310053, China E-mail: [email protected] The authors apologize for any inconvenience or misunderstanding that this error may have caused.

Prognostic significance of radiologic features of pneumonitis induced by anti-PD-1 therapy.

9065 Background: Anti-PD-1 therapy is now a standard treatment for patients with NSCLCs. Pneumonitis induced by immune-check point inhibitors is potentially fatal; however, some studies have shown that antitumor effects were enhanced in patients with pneumonitis. Although several radiologic patterns of pneumonitis induced by anti-PD-1 therapy have been reported, the association between radiologic features and clinical outcomes, especially enhancement of antitumor effects remains unclear. Methods: We retrospectively evaluated data of NSCLC patients treated in 1st to 3rd line with anti-PD-1 antibodies (nivolumab or pembrolizumab) at Niigata Lung Cancer Treatment Group. Pneumonitis was diagnosed by the treating investigators. The chest CT scans of patients with pneumonitis were independently reviewed by one radiologist and two pulmonologists to classify pneumonitis into 5 subtypes: cryptogenic organizing pneumonia-like (COP), ground glass opacities (GGO), interstitial, hypersensitivity and pneumonitis not otherwise specified (NOS). Results: Of 231 patients who received anti-PD-1 antibodies, pneumonitis developed in 33 patients (14.3%) at 7 institutions between January 2016 to October 2017. Of 33 patients with pneumonitis, the median age was 66 (range 45 to 82 years), 7 were female, 25 received nivolumab, and 8 received pembrolizumab. Sixteen patients were classified as GGO, 16 patients had COP-like appearance and one patient had NOS. The median survival time was significantly longer among patients with COP than among those with GGO (not reached vs. 7.8 months; HR 0.29, 95% CI 0.09-0.81; p = 0.0071). Pneumonitis improved in 94% (31 of 33) of cases, and one patient died from pneumonitis. The overall response ratio (CR+PR) was 44% in patients with COP and 31% in patients with GGO (p = 0.47). There was no statistical difference in OS between patients with systemic corticosteroid therapy for pneumonitis and those without (not reached vs. 14.8 months; HR 1.4, 95% CI 0.52-4.1; p = 0.51). Conclusions: Patients with pneumonitis classified as COP had significantly longer survival time than those with pneumonitis classified as GGO. Radiologic features of pneumonitis may reflect clinical outcomes after anti-PD-1 therapy.

From Nanofibers to Nanorods: Nanostructure of Peptide‐Drug Conjugates Regulated by Polypeptide‐PEG Derivative and Enhanced Antitumor Effect

AbstractPeptide‐drug conjugates (PDCs) are a type of self‐assembled prodrug with good potential for drug delivery due to their excellent biocompatibility, high drug loading, and permanent controllable release. However, most PDCs tend to self‐assemble into filamentous nanostructures in water and under physiological conditions, making them unsuitable as intravenous formulations due to the entanglement of long fibers and the risk of thrombus. Injected PDCs also face challenges in overcoming the complex physiological environment to reach the target site. To expand their clinical use, it is necessary to control the properties of PDC, including the self‐assembled structure and physiological performance, to avoid the above problems. Based on assembly mechanism studies of PDCs, a new method for regulating PDC morphology is developed by controlling intermolecular interactions in the assembly process. This method can alter the final morphology of PDCs from nanofibers to nanorods, and the introduced macromolecules endow the PDC with new characteristics that facilitate stable and high‐efficiency access to the target site.

Enhancement of anti-tumor effect of plasmid DNA-carrying MUC1 by the adjuvanticity of FLT3L in mouse model

Aim: DNA vaccines have emerged as a promising strategy for cancer immunotherapy; however, their immunogenicity is weak. Fms-like tyrosine kinase 3-ligand (Flt3L) has been exploited for its ability to increase the proliferation of dendritic cells (DCs). The aim of the present study was to investigate whether co-administration of an adjuvant plasmid expressing mouse Flt3L and a DNA vaccine of the Mucin 1 (MUC1) antigen enhances immune responses.Methods: The recombinant plasmids pVAX1-MUC1 and pVAX1-Flt3L were constructed and injected into mice intramuscularly (i.m.), followed by electroporation. The humoral and cellular immune responses after immunization were examined by enzyme linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT), respectively. To evaluate the anti-tumor efficacy of the plasmids, a mouse model of MUC1-expressing tumors was established.Results: The results showed that co-administration of an adjuvant plasmid and a DNA vaccine stimulated the production of higher titers of specific antibodies and a T cell response and suppressed the growth of subcutaneous tumors expressing MUC1. Collectively, our results indicate that a plasmid expressing murine Flt3L could stimulate stronger immune responses.Conclusion: These observations emphasize the potential of Flt3L as an adjuvant for colon cancer DNA vaccines.

Abstract 5654: Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy

Abstract Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) blockade therapy has demonstrated to enhance antitumor immunity. Recent evidence has shown that anti-PD-1/PD-L1 therapy restores the function of exhausted effector T cells and augments antitumor immune responses. The expression of PD-L1 has been best studied as a biomarker for the anti-PD-1/PD-L1 therapy. Because PD-L1 expression on tumor cells is induced by IFN-γ which is mainly produced by effector T cells, induction of antitumor effector T cells in cancer patients could be an important for the anti-PD-1/PD-L1 therapy. Indeed, previous studies have suggested that the increase of tumor-infiltrating lymphocytes is the predictive biomarker for PD-1/PD-L1 blockade therapy. We and others have demonstrated that lymphodepletive therapies, such as chemotherapy and radiotherapy, induce tumor-specific effector T cells from naïve T cells. Naïve T cells rapidly proliferate and elicit memory-like functions after lymphodepletion (homeostatic proliferation). These findings indicate that lymphodepletive regimens could augment the antitumor efficacies of the anti-PD-1/PD-L1 therapy. In the current study, we transferred naïve T cells into mice after whole-body irradiation or chemotherapy. These mice were inoculated s.c. with PD-L1+ B16F10 melanoma cells or PD-L1- MCA205 fibrosarcoma and then were treated with anti-PD-1 mAbs. Lymphodepletion by whole body irradiation, but not cytotoxic agents following the transfer of naïve T cells significantly enhanced antitumor immunity of anti-PD-1 mAbs. This augmentation required both of CD4+ and CD8+ T cells, but not NK cells. Further experiments revealed that immune cells infiltrating MCA205 expressed PD-L1. Transfer of naïve T cells from IFN-γ knockout mice abrogated the enhancement of antitumor effects of anti-PD-1 mAb therapy by lymphodepletion. These results suggest that lymphodepletion induces homeostatic proliferation of T cells and augments antitumor effects of PD-1/PD-L1 blockade therapy. Citation Format: Masashi Arita, Satoshi Watanabe, Takahashi Miho, Miyuki Sato, Aya Ohtsubo, Kosuke Ichikawa, Rie Kondo, Tetsuya Abe, Junta Tanaka, Toshiyuki Koya, Toshiaki Kikuchi. Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5654. doi:10.1158/1538-7445.AM2017-5654

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non-Small Cell Lung Cancer.

CD47-specific antibodies and fusion proteins that block CD47-SIRPα signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in non-small cell lung cancer (NSCLC). SIRPαD1-Fc, a novel CD47-targeting fusion protein, was generated and was found to increase the phagocytic and cytotoxic activities of macrophages against NSCLC cells. During this process, autophagy was markedly triggered, which was characterized by the three main stages of autophagic flux, including formation and accumulation of autophagosomes, fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Meanwhile, reactive oxygen species and inactivation of mTOR were shown to be involved in autophagy initiation in SIRPαD1-Fc-treated cells, indicating a probable mechanism for autophagy activation after targeting CD47 by SIRPαD1-Fc. Inhibition of autophagy enhanced macrophage-mediated phagocytosis and cytotoxicity against SIRPαD1-Fc-treated NSCLC cells. In addition, simultaneously targeting both CD47 and autophagy in NSCLC xenograft models elicited enhanced antitumor effects, with recruitment of macrophages, activated caspase-3, and overproduction of ROS at the tumor site. Our data elucidated the cytoprotective role of autophagy in CD47-targeted therapy and highlighted the potential approach for NSCLC treatment by simultaneously targeting CD47 and autophagy. Cancer Immunol Res; 5(5); 363-75. ©2017 AACRSee related Spotlight by Kaufman, p. 355.

148 - IDO1 Immune Checkpoint Inhibitor Synergizes with Radiation to Enhance Antitumor Effect in Colorectal Cancer in vitro and in Syngeneic Model

148 - IDO1 Immune Checkpoint Inhibitor Synergizes with Radiation to Enhance Antitumor Effect in Colorectal Cancer in vitro and in Syngeneic Model