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1.
Int J Pharm ; 628: 122361, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36332828

RESUMO

PD-1/L1 checkpoint blockade has gained approval in terms of treating patients suffering from hepatocellular carcinoma (HCC). It should be noted that the PD-1/L1 inhibitor (α-PD-1/L1) has a low overall response rate when used as a single agent. Accordingly, the combination of α-PD-1/L1 and a series of therapies to further increase the response rate has become a major research direction. In our previous study, we developed a novel norcantharidin (NCTD) liposome emulsion hybrid delivery system (NE) with enhanced anticancer activity and reduced toxicity. In this study, NE was combined with α-PD-1/L1 for treating HCC. The combination therapy exhibited an enhanced antitumor activity, which led to the up-regulated expression levels of white blood cells, interleukin 12 (IL-12), interferon γ (IFN-γ), PD-L1, as well as CD8. Furthermore, the combination of NE and α-PD-1 achieved the optimal efficiency. NCTD-based chemotherapy is capable of synergizing with α-PD-1/L1 while enhancing checkpoint immunotherapy. It follows a mechanism that NCTD agonizes the non-canonical NF-κB pathway of dendritic cells for better activating CD8+T cells. Furthermore, NCTD may enhance antitumor immunity due to the leukogenic effect. In brief, new therapeutic regimens were provided for anti-HCC treatment by integrating NE to PD-1/L1 immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1 , Receptor de Morte Celular Programada 1/metabolismo , Lipossomos/uso terapêutico , NF-kappa B , Emulsões , Carcinoma Hepatocelular/patologia , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Linhagem Celular Tumoral
2.
Front Immunol ; 13: 1012499, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341340

RESUMO

The trans-membrane proteins of the B7 family programmed cell death ligand-1 (PD-L1) and programmed death-1 (PD-1) play important roles in inhibiting immune responses and enhancing self-tolerance via T-cell modulation. Several therapeutic antibodies are used to promote T-cell proliferation by preventing interactions between PD-1/PD-L1. Recombinant technology appears to be quite useful in the production of such potent antibodies. In this study, we constructed recombinant molecules by cloning variable regions of the PD-L1 molecule into pMH3 vectors and transferring them into mammalian cell lines for expression. G418 supplementation was used to screen the recombinant clones, which were then maintained on serum-free medium. The full-length antibody was isolated and purified from the medium supernatant at a concentration of 0.5-0.8 mg/ml. Antibody binding affinity was investigated using ELISA and immunofluorescence methods. The protein-protein interactions (PPI) were determined using a docking approach. The SWISS model was utilized for homology modeling, while ZDOCK, Chimera, and PyMOL were used to validate 3D models. The Ramachandran plots were constructed using the SWISS model, which revealed that high-quality structures had a value of more than 90%. Current technologies allow for the accurate determination of antigen-antibody interactions.


Assuntos
Anticorpos Monoclonais , Antígeno B7-H1 , Animais , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Ligantes , Bioengenharia , Apoptose , Mamíferos
3.
Front Immunol ; 13: 1026214, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341395

RESUMO

Evidence increasingly indicated that lung cancer incidence in female individuals continue to rise, and women have a higher risk to develop adenocarcinoma than men. Male and female individuals differ in their innate and adaptive immune responses, and there are sex differences in response to the PD-1/PD-L1-dependent blocking immunotherapy. Whether the differential expression of PD-1 between genders affect the response to blocking treatment is currently unknown. In this study, we examined sex differences in serum sPD-1, mPD-1 expression on T cells, and sex hormone levels in non-small cell lung cancer (NSCLC) patients. Our results revealed a higher level of sPD-1 and expression of PD-1 on CD4+T cell in female patients than in male patients; we identified that serum sPD-1 level and the expression of mPD-1 on T cells were significantly reduced in NSCLC; we also found that serum testosterone level increased in female patients compared with control subjects and that increased testosterone downregulated the expression of mPD-1 on T cell. These findings provide a better understanding of the differences in PD-1 expression between genders in NSCLC patients and the effect of sex hormones on PD-1 expression and supply evidence for early lung cancer diagnosis and responsiveness to immune checkpoint inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Caracteres Sexuais , Testosterona
4.
Sci Rep ; 12(1): 18509, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323740

RESUMO

PD-1 immune checkpoint blockade against inhibitory receptors such as receptor programmed cell death-1 (PD-1), has revolutionized cancer treatment. Effective immune reactivity against tumour antigens requires the infiltration and activation of tumour-infiltrating T-cells (TILs). In this context, ligation of the antigen-receptor complex (TCR) in combination with the co-receptor CD28 activates the intracellular mediator AKT (or PKB, protein kinase B) and its downstream targets. PD-1 inhibits the activation of AKT/PKB. Given this, we assessed whether the direct activation of AKT might be effective in activating the immune system to limit the growth of tumors that are resistant to PD-1 checkpoint blockade. We found that the small molecule activator of AKT (SC79) limited growth of a B16 tumor and an EMT-6 syngeneic breast tumor model that are poorly responsive to PD-1 immunotherapy. In the case of B16 tumors, direct AKT activation induced (i) a reduction of suppressor regulatory (Treg) TILs and (ii) an increase in effector CD8+ TILs. SC79 in vivo therapy caused a major increase in the numbers of CD4+ and CD8+ TILs to express interferon-γ (IFN-γ). This effect on IFN-γ expression distinguished responsive from non-responsive anti-tumor responses and could be recapitulated ex vivo with human T-cells. In CD4+FoxP3+Treg TILs, AKT induced IFN-γ expression was accompanied by a loss of suppressor activity, the conversation to CD4+ helper Th1-like TILs and a marked reduction in phospho-SHP2. In CD8+ TILs, we observed an increase in the phospho-activation of PLC-γ. Further, the genetic deletion of the transcription factor T-bet (Tbx21) blocked the increased IFN-γ expression on all subsets while ablating the therapeutic benefits of SC79 on tumor growth. Our study shows that AKT activation therapy acts to induce IFN-γ on CD4 and CD8 TILs that is accompanied by the intra-tumoral conversation of suppressive Tregs into CD4+Th1-like T-cells and augmented CD8 responses.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Interferon gama/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T CD8-Positivos , Neoplasias/patologia
5.
J Mater Chem B ; 10(44): 9249-9257, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36321642

RESUMO

Incomplete tumor ablation and subsequent tumor metastasis usually occur during photothermal anti-tumor processes. The combination of photothermal and immunotherapy has proven to be a promising method to conquer technical challenges. Inhibiting the programmed death ligand-1 (PD-L1)/programmed cell death protein 1 (PD-1) immune pathway represents one of the most successful immunotherapy strategies. Whereas, the PD-L1 expression level significantly differs, leading to a relatively low response rate to the immune checkpoint blockade (ICB) approaches. Therefore, improving the expression level of PD-L1 becomes one potential method to enhance the response rate. Herein, NIH 3T3 cells were educated to steadily express PD-1 protein. Furthermore, the synthesized molybdenum nitride was then coated with PD-1 protein-modified cytomembrane, which endows it with immune checkpoint blocking capability. Moreover, under the irradiation of near-infrared light, the local mild heat released from the molybdenum nitride causes the apoptosis of tumor cells. More importantly, the elevated temperature simultaneously helps elevate the expression level of PD-L1, further enhancing the response rate of ICB. Finally, the PD-1 cytomembrane coatings interact with the upregulated PD-L1, leading to the activation of the immune system. In summary, we confirmed that the PD-1 protein-coated molybdenum nitride could synergistically ablate tumors and avoid metastasis.


Assuntos
Neoplasias da Mama , Hipertermia Induzida , Camundongos , Animais , Humanos , Feminino , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Mama/terapia , Molibdênio/farmacologia , Imunoterapia , Fatores Imunológicos
6.
Nature ; 611(7935): 358-364, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323784

RESUMO

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases1. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.


Assuntos
Envelhecimento , Antígeno B7-H1 , Fenótipo , Receptor de Morte Celular Programada 1 , Animais , Camundongos , Envelhecimento/imunologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Inflamação/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Análise de Célula Única , Hepatopatia Gordurosa não Alcoólica , Fígado , Rejuvenescimento
7.
Cell Rep ; 41(7): 111647, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36384131

RESUMO

Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.


Assuntos
Doença Enxerto-Hospedeiro , Interferon Tipo I , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1/metabolismo , Peroxidação de Lipídeos , Neoplasias/metabolismo , Interferon Tipo I/metabolismo , Lipídeos
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(11): 1036-1043, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36328434

RESUMO

The immune checkpoint, programmed death 1 ligand-1/programmed death -1 (PD-L1/PD-1), is one of the most promising targets for tumor immunotherapy. Overexpressed PD-L1 on the surface of tumor cells could bind to PD-1 on the surface of T cells and inhibit the T cell activation, triggering tumor-immune-escape; therapeutic strategies targeting PD-1/PD-L1 restore the cytotoxic function of immune cells in the tumors by blocking PD-1/PD-L1 interaction. The PD-L1 undergoes multi-level regulations in tumor cells. Among them, post-translational modifications (PTMs) of PD-L1 mainly including glycosylation, phosphorylation, ubiquitination, acetylation and palmitoylation, have attracted much attention in recent years. These modifications directly affect the stability, cellular localization and function of PD-L1, and subsequently regulate the T cell activation and tumor immunity. Therefore, intervention with PTMs of PD-L1 may serve as a new approach for anti-tumor immunity-escape therapy.


Assuntos
Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/genética , Receptor de Morte Celular Programada 1/metabolismo , Imunoterapia , Neoplasias/terapia , Processamento de Proteína Pós-Traducional , Microambiente Tumoral
10.
Biochem Biophys Res Commun ; 636(Pt 1): 140-146, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36332476

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM2), which is typically expressed in microglia/macrophage, is a crucial receptor modulating the activation of immune cells. Recent single-cell RNA sequencing studies of the tumor microenvironment (TME) have found that TREM2 is highly expressed in several subgroups of tumor-associated macrophages (TAMs) with immunosuppressive activity. TREM2 knockout mice are more resistant to tumor growth than wild-type mice in multiple mice tumor models. But the function of TREM2 expression in TAMs of hepatocellular carcinoma (HCC) is still unclear. Here we used a self-complementary adeno-associated virus (scAAV) with macrophage tropism to efficiently knockdown TREM2 in TAMs in vivo and found that the growth of hepatocellular carcinoma was suppressed by TREM2 knockdown. Moreover, we found that TREM2 knockdown remodeled TAMs to an immune-stimulating status and enhanced the therapeutic effect of PD-1 immune-checkpoint blockade in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológico , Macrófagos/metabolismo , Microambiente Tumoral , Camundongos Knockout , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
11.
Cells ; 11(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36359830

RESUMO

Lung cancer is among the most common and lethal cancers and warrants novel therapeutic approaches to improving patient outcomes. Although immune checkpoint inhibitors (ICIs) have demonstrated substantial clinical benefits, most patients remain unresponsive to currently approved ICIs or develop resistance after initial response. Many ongoing clinical studies are investigating combination therapies to address the limited efficacy of ICIs. Here, we have assessed whether p53 gene therapy via a tumor-targeting nanomedicine (termed SGT-53) can augment anti-programmed cell death-1 (PD-1) immunotherapy to expand its use in non-responding patients. Using syngeneic mouse models of lung cancers that are resistant to anti-PD-1, we demonstrate that restoration of normal p53 function potentiates anti-PD-1 to inhibit tumor growth and prolong survival of tumor-bearing animals. Our data indicate that SGT-53 can restore effective immune responses against lung cancer cells by reducing immuno-suppressive cells (M2 macrophages and regulatory T cells) and by downregulating immunosuppressive molecules (e.g., galectin-1, a negative regulator of T cell activation and survival) while increasing activity of cytotoxic T cells. These results suggest that combining SGT-53 with anti-PD-1 immunotherapy could increase the fraction of lung cancer patients that responds to anti-PD-1 therapy and support evaluation of this combination particularly in patients with ICI-resistant lung cancers.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Proteína Supressora de Tumor p53/genética , Nanomedicina , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Terapia de Imunossupressão
12.
Front Immunol ; 13: 982902, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405753

RESUMO

Programmed death-ligand 1 (PD-L1) is a transmembrane protein with essential roles in the suppression of adaptive immune responses. As an immune checkpoint molecule, PD-L1 can be exploited by cancer cells to evade the anti-tumor attacks initiated by the immune system. Thus, blockade of the PD1/PD-L1 axis can eliminate the suppressive signals and release the antitumor immune responses. Identification of the underlying mechanisms of modulation of the activity of the PD1/PD-L1 axis would facilitate the design of more efficacious therapeutic options and better assignment of patients for each option. Recent studies have confirmed the interactions between miRNAs/lncRNAs/circ-RNAs and the PD1/PD-L1 axis. In the current review, we give a summary of interactions between these transcripts and PD-L1 in the context of cancer. We also overview the consequences of these interactions in the determination of the response of patients to anti-cancer drugs.


Assuntos
MicroRNAs , Neoplasias , Humanos , Antígeno B7-H1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias/metabolismo , MicroRNAs/genética , MicroRNAs/uso terapêutico
13.
Front Immunol ; 13: 1022011, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405757

RESUMO

The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response's activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Animais , Camundongos , Radioimunoterapia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Imunoterapia
14.
Sci Rep ; 12(1): 17792, 2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36273231

RESUMO

Programmed cell death protein 1 (PD-1) plays a significant role in suppressing antitumor immune responses. Cancer treatment with immune checkpoint inhibitors (ICIs) targeting PD-1 has been approved to treat numerous cancers and is the backbone of cancer immunotherapy. Anti-PD-1 molecule is necessary for next-generation cancer immunotherapy to further improve clinical efficacy and safety as well as integrate into novel treatment combinations or platforms. We developed a highly efficient hybridoma generation and screening strategy to generate high-potency chimeric anti-PD-1 molecules. Using this strategy, we successfully generated several mouse hybridoma and mouse/human chimeric clones that produced high-affinity antibodies against human PD-1 with high-quality in vitro PD-1/PD-L1 binding blockade and T cell activation activities. The lead chimeric prototypes exhibited overall in vitro performance comparable to commercially available anti-PD-1 antibodies and could be qualified as promising therapeutic candidates for further development toward immuno-oncology applications.


Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Camundongos , Animais , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico , Hibridomas , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico
15.
Sci Rep ; 12(1): 18011, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289396

RESUMO

Programmed death-ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two potential targets for cancer immunotherapy, early clinical studies showed the combination therapy of anti-PD-L1 and anti-TIGIT had synergistic efficacy both in the terms of overall response rate (ORR) and overall survival (OS). It is rational to construct bispecific antibodies targeting PD-L1 and TIGIT, besides retaining the efficacy of the combination therapy, bispecific antibodies (BsAbs) can provide a new mechanism of action, such as bridging between tumor cells and T/NK cells. Here, we developed an IgG1-type bispecific antibody with optimal cytotoxicity. In this study, we thoroughly investigated 16 IgG-VHH formats with variable orientations and linker lengths, the results demonstrated that (G4S)2 linker not only properly separated two binding domains but also had the highest protein yield. Moreover, VHH-HC orientation perfectly maintained the binding and cytotoxicity activity of the variable domain of the heavy chain of heavy-chain-only antibody (VHH) and immunoglobulin G (IgG). Following treatment with BiPT-23, tumor growth was significantly suppressed in vivo, with more cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells infiltration, and selective depletion of Regulatory T cells (Tregs). BiPT-23 represents novel immunotherapy engineered to prevent hyperprogression of cancer with PD-1 blockade, and preferentially killed PD-L1+ tumor cells, and TIGIT+ Tregs but maintained CD11b+F4/80+ immune cells within the tumor microenvironment (TME).


Assuntos
Anticorpos Biespecíficos , Neoplasias , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imunoglobulina G/uso terapêutico , Microambiente Tumoral , Receptores Imunológicos
16.
Cells ; 11(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36291098

RESUMO

BACKGROUND: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). METHODS: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion. RESULTS: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs. CONCLUSION: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.


Assuntos
Neoplasias Pulmonares , Subpopulações de Linfócitos T , Humanos , Antígeno B7-H1/metabolismo , Líquido da Lavagem Broncoalveolar , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/imunologia
18.
Int J Mol Sci ; 23(20)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36293034

RESUMO

Malignant pleural effusion (MPE) provides a liquid tumor microenvironment model that includes cancer cells and immune cells. However, the characteristics of tumor antigen-specific CD8+ T cells have not been investigated in detail. Here, we analyzed MPE samples taken from a patient with pancreatic cancer who received a dendritic cell vaccine targeting Wilms' Tumor 1 (WT1) antigen over the disease course (two points at MPE1st and 2nd, two months after MPE1st). Epithelial cell adhesion molecule (EpCAM)+ cancer cells (PD-L1- or T cell immunoglobulin mucin-3, TIM-3-), both PD-1 or TIM-3 positive CD8+ T cells, and CD14+CD68+CD163+TIM-3+ macrophages increased from the MPE1st to MPE2nd. The ratio of WT1-specific cytotoxic lymphocytes (WT1-CTLs) to MPE CD8+ T cells and IFN-γ secretion of WT1-CTLs were reduced with disease progression. Coincidentally, the fraction of central memory T (TCM) of WT1-CTLs was decreased. On the other hand, CD8+ T cells in response to SMAD4P130L, which is homogeneously expressed in EpCAM+ cancer cells, were detected using in vitro expansion with the HLA-A*11:01 restrictive SVCVNLYH neoantigen. Furthermore, the CD8+ T cell response to SMAD4P130L was diminished following remarkably decreased numbers of CD8+ TCM in MPE samples. In conclusion, CD8+ T cells responding to WT1 or SMAD4P130L neoantigen expressed in EpCAM+ pancreatic cancer cells were detected in MPE. A tumor antigen-specific immune response would provide novel insight into the MPE microenvironment.


Assuntos
Neoplasias Pancreáticas , Derrame Pleural Maligno , Vacinas , Humanos , Molécula de Adesão da Célula Epitelial/metabolismo , Linfócitos T CD8-Positivos , Antígeno B7-H1/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Proteínas WT1 , Receptor de Morte Celular Programada 1/metabolismo , Mucina-3/metabolismo , Neoplasias Pancreáticas/patologia , Imunoglobulinas/metabolismo , Vacinas/metabolismo , Antígenos HLA-A , Microambiente Tumoral , Proteína Smad4/metabolismo
19.
Front Immunol ; 13: 955063, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248850

RESUMO

Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body's immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures. We performed multi-omics investigations on melanoma tumour tissues, which were collected from patients before starting treatment with anti-PD1 immune checkpoint inhibitors. Patients were subsequently categorized into responders and non-responders to anti-PD1 therapy based on RECIST criteria. Multi-omics analyses included RNA-Seq and NanoString analysis. From RNA-Seq data we carried out HLA phenotyping as well as gene enrichment analysis, pathway enrichment analysis and immune cell deconvolution studies. Consistent with previous studies, our data showed that responders to anti-PD1 therapy had higher immune scores (median immune score for responders = 0.1335, median immune score for non-responders = 0.05426, p-value = 0.01, Mann-Whitney U two-tailed exact test) compared to the non-responders. Responder melanomas were more highly enriched with a combination of CD8+ T cells, dendritic cells (p-value = 0.03) and an M1 subtype of macrophages (p-value = 0.001). In addition, melanomas from responder patients exhibited a more differentiated gene expression pattern, with high proliferative- and low invasive-associated gene expression signatures, whereas tumours from non-responders exhibited high invasive- and frequently neural crest-like cell type gene expression signatures. Our findings suggest that non-responder melanomas to anti-PD1 therapy exhibit a de-differentiated gene expression signature, associated with poorer immune cell infiltration, which establishes a gene expression pattern characteristic of innate resistance to anti-PD1 therapy. Improved understanding of tumour-intrinsic gene expression patterns associated with response to anti-PD1 therapy will help to identify predictive biomarkers of ICI response and may help to identify new targets for anticancer treatment, especially with a capacity to function as adjuvants to improve ICI outcomes.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Transcriptoma
20.
Front Immunol ; 13: 940577, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248873

RESUMO

Background: Aging is usually accompanied by functional declines of the immune system, especially in T-cell responses. However, little is known about ways to alleviate this. Methods: Here, 37 middle-aged healthy participants were recruited, among which 32 were intravenously administrated with expanded NK cells and 5 with normal saline. Then, we monitored changes of peripheral senescent and exhausted T cells within 4 weeks after infusion by flow cytometry, as well as serum levels of senescence-associated secretory phenotype (SASP)-related factors. In vitro co-culture assays were performed to study NK-mediated cytotoxic activity against senescent or exhausted T cells. Functional and phenotypic alteration of NK cells before and after expansion was finally characterized. Results: After NK cell infusion, senescent CD28-, CD57+, CD28-CD57+, and CD28-KLRG1+ CD4+ and CD8+ T-cell populations decreased significantly, so did PD-1+ and TIM-3+ T cells. These changes were continuously observed for 4 weeks. Nevertheless, no significant changes were observed in the normal saline group. Moreover, SASP-related factors including IL-6, IL-8, IL-1α, IL-17, MIP-1α, MIP-1ß, and MMP1 were significantly decreased after NK cell infusion. Further co-culture assays showed that expanded NK cells specifically and dramatically eliminated senescent CD4+ T cells other than CD28+CD4+ T cells. They also showed improved cytotoxic activity, with different expression patterns of activating and inhibitory receptors including NKG2C, NKG2A, KLRG1, LAG3, CD57, and TIM3. Conclusion: Our findings imply that T-cell senescence and exhaustion is a reversible process in healthy individuals, and autologous NK cell administration can be introduced to alleviate the aging. Clinical Trial Registration: ClinicalTrials.gov, ChiCTR-OOh-17011878.


Assuntos
Antígenos CD28 , Receptor Celular 2 do Vírus da Hepatite A , Antígenos CD28/metabolismo , Quimiocina CCL3/metabolismo , Quimiocina CCL4/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Células Matadoras Naturais , Metaloproteinase 1 da Matriz/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Solução Salina/metabolismo
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