RESUMO
PD-L1 has two receptors: PD-1 and CD80. Previous reports assumed that PD-L1 and CD80 interacted in trans, but recent reports showed that only cis PD-L1/CD80 interactions existed, and prevention of cis PD-L1/CD80 interactions on antigen-presenting cells (APCs) reduced antitumor immunity via augmenting PD-L1/PD-1 and CD80/CTLA4 interactions between T and APCs. Here, using tumor-bearing mice capable of cis and trans or trans only PD-L1/CD80 interactions, we show that trans PD-L1/CD80 interactions do exist between tumor and T cells, and the effects of trans PD-L1/CD80 interactions require tumor cell expression of MHC-I and T cell expression of CD28. The blockade of PD-L1/CD80 interactions in mice with both cis and trans interactions or with only trans interactions augments antitumor immunity by expanding IFN-γ-producing CD8+ T cells and IFN-γ-dependent NOS2-expressing tumor-associated macrophages. Our studies indicate that although cis and trans PD-L1/CD80 interactions may have opposite effects on antitumor immunity, the net effect of blocking PD-L1/CD80 interactions in vivo augments CD8+ T cell-mediated antitumor immunity.
Assuntos
Antígeno B7-H1 , Linfócitos T CD8-Positivos , Camundongos , Animais , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Ativação Linfocitária , Antígeno B7-1 , Moléculas de Adesão CelularRESUMO
Early identification of safe and efficacious disease targets is crucial to alleviating the tremendous cost of drug discovery projects. However, existing experimental methods for identifying new targets are generally labor-intensive and failure-prone. On the other hand, computational approaches, especially machine learning-based frameworks, have shown remarkable application potential in drug discovery. In this work, we propose Progeni, a novel machine learning-based framework for target identification. In addition to fully exploiting the known heterogeneous biological networks from various sources, Progeni integrates literature evidence about the relations between biological entities to construct a probabilistic knowledge graph. Graph neural networks are then employed in Progeni to learn the feature embeddings of biological entities to facilitate the identification of biologically relevant target candidates. A comprehensive evaluation of Progeni demonstrated its superior predictive power over the baseline methods on the target identification task. In addition, our extensive tests showed that Progeni exhibited high robustness to the negative effect of exposure bias, a common phenomenon in recommendation systems, and effectively identified new targets that can be strongly supported by the literature. Moreover, our wet lab experiments successfully validated the biological significance of the top target candidates predicted by Progeni for melanoma and colorectal cancer. All these results suggested that Progeni can identify biologically effective targets and thus provide a powerful and useful tool for advancing the drug discovery process.
Assuntos
Biologia Computacional , Descoberta de Drogas , Aprendizado de Máquina , Redes Neurais de Computação , Humanos , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Algoritmos , Melanoma , Probabilidade , Neoplasias ColorretaisRESUMO
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Evasão Tumoral/imunologia , Animais , Apolipoproteínas E/metabolismo , Arginase/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , Tolerância Imunológica/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores Imunológicos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The immunological components that control resolution of Salmonella infection and successful vaccination are poorly defined. In a model of chronic gastrointestinal infection, we observed that the lymphotoxin (LT) pathway is essential for the clearance and resolution of primary infection of attenuated Salmonella enterica Typhimurium strain SL3261 ΔaroA Using gnotobiotic mice, we show that LTß receptor (LTßR) signaling and the microbiota are required to promote clearance of attenuated S. enterica Typhimurium from the gut lumen. We also found that LTßR signaling was required for successful immunization and subsequent protection upon challenge with a virulent strain of S enterica Typhimurium. LTßR signaling promoted the development of specific IgG recognizing S enterica Typhimurium during infection, as well as Ag-driven IFN-γ responses. B cell- and type 3 innate lymphoid cell-derived LT signaling, but not T cell-derived LT, contributes to anti-S enterica Typhimurium protective responses. Collectively, our results suggest that LT signaling is essential for multiple steps of anti-S enterica Typhimurium immune responses.
Assuntos
Microbioma Gastrointestinal/imunologia , Linfotoxina-alfa/imunologia , Salmonelose Animal/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Vida Livre de Germes , Camundongos , Salmonella typhimurium/imunologia , Transdução de Sinais/imunologiaRESUMO
We previously showed that LIGHT and its receptor herpes virus entry mediator (HVEM) are important for development of optimal CD4(+) Th1 cell immunity and resistance to primary Leishmania major infection in mice. In this study, we further characterized the contributions of this molecule in dendritic cell (DC) maturation, initiation, and maintenance of primary immunity and secondary anti-Leishmania immunity. Flow-cytometric studies showed that CD8α(+) DC subset was mostly affected by HVEM-Ig and lymphotoxin ß receptor-Ig treatment. LIGHT signaling is required at both the priming and the maintenance stages of primary anti-Leishmania immunity but is completely dispensable during secondary immunity in wild type mice. However, LIGHT blockade led to impaired IL-12 and IFN-γ responses and loss of resistance in healed CD40-deficient mice after L. major challenge. The protective effect of LIGHT was mediated primarily via its interaction with lymphotoxin ß receptor on CD8α(+) DCs. Collectively, our results show that although LIGHT is critical for maintenance of primary Th1 response, it is dispensable during secondary anti-Leishmania immunity in the presence of functional CD40 signaling as seen in wild type mice.
Assuntos
Antígenos CD40/deficiência , Interações Hospedeiro-Patógeno/imunologia , Leishmaniose Cutânea/imunologia , Células Th1/imunologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/parasitologia , Células da Medula Óssea/patologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Antígenos CD8/genética , Antígenos CD8/imunologia , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Células Dendríticas/patologia , Feminino , Regulação da Expressão Gênica , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Leishmania major/imunologia , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/imunologia , Camundongos , Transdução de Sinais , Células Th1/parasitologia , Células Th1/patologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
The granule exocytosis pathway of cytotoxic lymphocytes plays critical roles in eradication of intracellular viruses. However, how hepatitis B virus (HBV) is cleared has not been defined. To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between granzyme H (GzmH) and HBV clearance was investigated. In this study, we found that the granule exocytosis pathway can inhibit HBV replication without induction of cytolysis of the infected cells. GzmH is essential for HBV eradication. The HBx protein (HBx), required for the replication of HBV, is cleaved at Met(79) by GzmH. GzmH inhibitor can abolish GzmH- and lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. An HBx-deficient HBV is resistant to GzmH- and lymphokine-activated killer cell-mediated viral clearance. Adoptive transfer of GzmH-overexpressing NK cells into HBV carrier mice facilitates in vivo HBV eradication. Importantly, low GzmH expression in cytotoxic lymphocytes of individuals is susceptible to HBV infection and hepatocellular carcinoma. These results indicate that GzmH might be detected as a potential parameter for diagnosis of HBV infection and hepatocellular carcinoma.
Assuntos
Granzimas/fisiologia , Vírus da Hepatite B/imunologia , Transativadores/antagonistas & inibidores , Transativadores/metabolismo , Replicação Viral/imunologia , Transferência Adotiva , Animais , Células Matadoras Induzidas por Citocinas/imunologia , Regulação Viral da Expressão Gênica/imunologia , Granzimas/biossíntese , Granzimas/genética , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transativadores/deficiência , Proteínas Virais Reguladoras e Acessórias , Replicação Viral/genéticaRESUMO
BACKGROUND: Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy. METHODS: We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo. RESULTS: Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery. CONCLUSIONS: Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.
Assuntos
Antineoplásicos , Diabetes Mellitus Tipo 2 , Neoplasias , Camundongos , Animais , Humanos , Dipeptidil Peptidase 4/metabolismo , Células Dendríticas , Fosfato de Sitagliptina/farmacologia , Fosfato de Sitagliptina/uso terapêutico , Fosfato de Sitagliptina/metabolismo , Apresentação de Antígeno , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunogenicidade da Vacina/imunologia , Ligação Proteica/imunologia , Domínios Proteicos/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antivirais/imunologia , Linhagem Celular , Chlorocebus aethiops , Método Duplo-Cego , Feminino , Células HEK293 , Humanos , Interferons/imunologia , Macaca mulatta , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Vacinação/métodos , Células Vero , Adulto JovemRESUMO
PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers. However, their effects on bone mass and bone metastasis are unknown. Here we show that olaparib increases breast cancer bone metastasis through PARP2, but not PARP1, specifically in the myeloid lineage, but not in the cancer cells. Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss. Intriguingly, myeloid deletion of PARP2, but not PARP1, increases the population of immature myeloid cells in bone marrow, and impairs the expression of chemokines such as CCL3 through enhancing the transcriptional repression by ß-catenin. Compromised CCL3 production in turn creates an immune-suppressive milieu by altering T cell subpopulations. Our findings warrant careful examination of current PARP inhibitors on bone metastasis and bone loss, and suggest cotreatment with CCL3, ß-catenin inhibitors, anti-RANKL or bisphosphonates as potential combination therapy for PARP inhibitors.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Reabsorção Óssea/patologia , Neoplasias da Mama/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CCL3/deficiência , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Feminino , Deleção de Genes , Humanos , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerases/deficiência , Regiões Promotoras Genéticas/genética , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.
Assuntos
Antígeno B7-H1/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ativação Linfocitária , Animais , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia , Regulação para CimaRESUMO
Accumulating data suggest an important role of tumor metabolism during cancer development, metastasis, and therapeutic resistance. In Cell Metabolism, Cascone et al. (2018) show that increased tumor glycolysis suppresses anti-tumor immunity by impairing T cell killing and trafficking to the tumor microenvironment.
Assuntos
Glicólise , Neoplasias , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Evasão da Resposta Imune , Microambiente TumoralRESUMO
Tumor microenvironments (TME) are usually immunosuppressive and prevent lymphocyte priming. Recent clinical trials have shown that cancer immunotherapy such as immune checkpoint inhibitors can induce unprecedented durable responses in patients with a variety of cancers. Tertiary lymphoid structures (TLS) can form inside or adjacent to tumor tissues due to persistent inflammation. The formation of TLS facilitates lymphocyte trafficking and infiltration into tumor tissues. It can also support effective antigen presentation and lymphocyte activation. Thus, TLS have become an intriguing target to manipulate antitumor immunity. Several therapeutics targeting TLS have been developed and shown promising antitumor effects in various mouse models. In this chapter, we describe the general approach to establish transplantable mouse tumor models for the study of immunotherapy. We introduce the strategies for therapy through systemic or local treatment targeting TLS. We also present approaches to evaluate the antitumor immune responses provoked by the therapies.
Assuntos
Imunoterapia , Neoplasias/imunologia , Neoplasias/patologia , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/patologia , Microambiente Tumoral/imunologia , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental , Camundongos , Neoplasias/metabolismo , Neoplasias/terapia , Estruturas Linfoides Terciárias/metabolismoRESUMO
Splenomegaly is a well-known phenomenon typically associated with inflammation. However, the underlying cause of this phenotype has not been well characterized. Furthermore, the splenomegaly phenotype seen in lymphotoxin (LT) signaling-deficient mice is characterized by increased numbers of splenocytes and splenic neutrophils. Splenomegaly, as well as the related phenotype of increased lymphocyte counts in non-lymphoid tissues, is thought to result from the absence of secondary lymphoid tissues in LT-deficient mice. We now present evidence that mice deficient in LTα1ß2 or LTßR develop splenomegaly and increased numbers of lymphocytes in non-lymphoid tissues in a microbiota-dependent manner. Antibiotic administration to LTα1ß2- or LTßR-deficient mice reduces splenomegaly. Furthermore, re-derived germ-free Ltbr-/- mice do not exhibit splenomegaly or increased inflammation in non-lymphoid tissues compared to specific pathogen-free Ltbr-/- mice. By using various LTß- and LTßR-conditional knockout mice, we demonstrate that retinoic acid-related orphan receptor γT-positive type 3 innate lymphoid cells provide the required active LT signaling to prevent the development of splenomegaly. Thus, this study demonstrates the importance of LT-mediated immune responses for the prevention of splenomegaly and systemic inflammation induced by microbiota.
Assuntos
Imunidade Inata , Linfócitos/imunologia , Heterotrímero de Linfotoxina alfa1 e beta2/imunologia , Receptor beta de Linfotoxina/imunologia , Microbiota/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Animais , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Linfócitos/patologia , Heterotrímero de Linfotoxina alfa1 e beta2/genética , Receptor beta de Linfotoxina/genética , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/genéticaRESUMO
Checkpoint blockade immunotherapy relies on energized cytotoxic T cells attacking tumour tissue systemically. However, for many cancers, the reliance on T cell infiltration leads to low response rates. Conversely, radiotherapy has served as a powerful therapy for local tumours over the past 100 years, yet is rarely sufficient to cause systemic tumour rejection. Here, we describe a treatment strategy that combines nanoscale metal-organic framework (nMOF)-enabled radiotherapy-radiodynamic therapy with checkpoint blockade immunotherapy for both local and systemic tumour elimination. In mouse models of breast and colorectal cancer, intratumorally injected nMOFs treated with low doses of X-ray irradiation led to the eradication of local tumours and, when loaded with an inhibitor of the immune checkpoint molecule indoleamine 2,3-dioxygenase, the irradiated nMOFs led to consistent abscopal responses that rejected distal tumours. By combining the advantages of local radiotherapy and systemic tumour rejection via synergistic X-ray-induced in situ vaccination and indoleamine 2,3-dioxygenase inhibition, nMOFs may overcome some of the limitations of checkpoint blockade in cancer treatment.
Assuntos
Imunoterapia/métodos , Estruturas Metalorgânicas/química , Nanoestruturas/química , Terapia por Raios X/métodos , Animais , Antineoplásicos , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Humanos , Estruturas Metalorgânicas/farmacologia , Camundongos , NanomedicinaRESUMO
Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.
Assuntos
Anticorpos/farmacologia , Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Imunoterapia , Interferon-alfa/farmacologia , Neoplasias/terapia , Animais , Feminino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Receptor de Interferon alfa e beta/metabolismo , Transdução de SinaisRESUMO
Programmed death-ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1-negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti-PD-L1-mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti-PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.
Assuntos
Antígeno B7-H1/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Anticorpos Monoclonais/imunologia , Células Apresentadoras de Antígenos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular , Linhagem Celular Tumoral , Citometria de Fluxo , Imunidade Celular , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Microambiente Tumoral/imunologiaRESUMO
The identification of critical DNA sensors and their pathways has led to revealing the central role of DNA sensing in immune system. It has been initially demonstrated that DNA sensing and immune responses have high impacts on the development and prevention of infection and inflammatory. In addition to toll-like receptor pathways, there is now also emerging evidence that cytosolic enzyme cyclic GMP-AMP synthase (cGAS) is essential for the recognition of not only pathogen-derived DNA but also tumor DNA for innate sensing. The strategies through activating DNA sensing pathways toward enhancing antitumor immunity have shown promise and are further tested in clinical studies. Here, we highlight recent progresses in understanding mechanisms activated by DNA sensing mediated immune responses in cancer therapy.
Assuntos
DNA de Neoplasias/imunologia , Imunidade Inata , Neoplasias/imunologia , Nucleotidiltransferases/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Animais , Humanos , Neoplasias/patologia , Neoplasias/terapiaRESUMO
Tertiary lymphoid structures (TLS) often develop at sites of persistent inflammation, including cancers and autoimmune diseases. In most cases, the presence of TLS correlates with active immune responses. Because of their proximity to pathological loci, TLS are an intriguing target for the manipulation of immune responses. For several years, it has become clear that lymphotoxin (LT) signalling plays critical roles in lymphoid tissue organogenesis and maintenance. In the current review, we will discuss the role of LT signalling in the development of TLS. With a focus on cancers and autoimmune diseases, we will highlight the correlations between TLS and disease progression. We will also discuss the current efforts and potential directions for manipulating TLS for immunotherapies.
Assuntos
Doenças Autoimunes/imunologia , Imunoterapia/métodos , Tecido Linfoide/fisiologia , Linfotoxina-alfa/metabolismo , Neoplasias/imunologia , Estruturas Linfoides Terciárias/imunologia , Animais , Carcinogênese , Progressão da Doença , Humanos , Organogênese , Transdução de SinaisRESUMO
Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases.