RESUMEN
Ionizing irradiation has been extensively employed for the clinical management of solid tumors, with therapeutic or palliative intents, for decades. Until recently, radiation therapy (RT) was believed to mediate antineoplastic activity mostly (if not only) as a consequence of cancer cell-intrinsic effects. Indeed, the macromolecular damage imposed to malignant cells by RT initiates one or multiple signal transduction cascades that drive a permanent proliferative arrest (cellular senescence) or regulated cell death. Both these phenomena show a rather linear dose-response correlation. However, RT also mediates consistent immunological activity, not only as an "on-target effect" originating within irradiated cancer cells, but also as an "off-target effect" depending on the interaction between RT and stromal, endothelial, and immune components of the tumor microenvironment. Interestingly, the immunological activity of RT does not exhibit linear dose-response correlation. Here, we discuss the mechanisms whereby RT alters the capacity of the immune system to recognize and eliminate irradiated cancer cells, either as an "on-target" or as on "off-target" effect. In particular, we discuss the antagonism between the immunostimulatory and immunosuppressive effects of RT as we delineate combinatorial strategies to boost the former at the expenses of the latter.
Asunto(s)
Muerte Celular , Citotoxicidad Inmunológica , Inmunidad , Neoplasias/radioterapia , Animales , Antígenos de Neoplasias/inmunología , Autofagia , Terapia Combinada , Humanos , Neoplasias/inmunología , Radiación Ionizante , Transducción de Señal , Microambiente TumoralRESUMEN
Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.
Asunto(s)
Citotoxicidad Inmunológica/inmunología , Inmunoterapia Adoptiva , Interleucina-15/farmacología , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/terapia , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Citocinas/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Activación de Linfocitos , Ratones Endogámicos NOD , Ratones SCID , Proteínas Mitocondriales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Transducción de SeñalRESUMEN
Gap junctions (GJs) mediate intercellular communication between adjacent cells. Previously, we showed that connexin 43 (Cx43), the main GJ protein in the immune system, mediates Ag transfer between human dendritic cells (DCs) and is recruited to the immunological synapse during T cell priming. This crosstalk contributed to T cell activation, intracellular Ca(2+) responses, and cytokine release. However, the role of GJs in NK cell activation by DCs and NK cell-mediated cytotoxicity against tumor cells remains unknown. In this study, we found polarization of Cx43 at the NK/DC and NK/tumor cell-contact sites, accompanied by the formation of functional GJs between NK/DCs and NK/tumor cells, respectively. Cx43-GJ-mediated intercellular communication (GJIC) between human NK and DCs was bidirectional. Blockage of Cx43-GJIC inhibited NK cell activation, though it affected neither the phenotype nor the function of DCs. Cx43 knockdown or inhibition using mimetic peptides greatly reduced CD69 and CD25 expression and IFN-γ release by DC-stimulated NK cells. Moreover, blocking Cx43 strongly inhibited the NK cell-mediated tumor cell lysis associated with inhibition of granzyme B activity and Ca(2+) influx. Our data identify a novel and active role for Cx43-GJIC in human NK cell activation and antitumor effector functions that may be important for the design of new immune therapeutic strategies.
Asunto(s)
Conexina 43/inmunología , Citotoxicidad Inmunológica/inmunología , Células Dendríticas/inmunología , Uniones Comunicantes/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Apoptosis , Señalización del Calcio , Comunicación Celular/inmunología , Línea Celular Tumoral , Conexina 43/antagonistas & inhibidores , Células Dendríticas/ultraestructura , Granzimas/fisiología , Humanos , Vigilancia Inmunológica , Sinapsis Inmunológicas/inmunología , Ensayos de Liberación de Interferón gamma , Células Asesinas Naturales/ultraestructuraRESUMEN
Adoptive infusion of natural killer (NK) cells is being increasingly explored as a therapy in patients with cancer, although clinical responses are thus far limited to patients with hematological malignancies. Inadequate homing of infused NK cells to the tumor site represents a key factor that may explain the poor anti-tumor effect of NK cell therapy against solid tumors. One of the major players in the regulation of lymphocyte chemotaxis is the chemokine receptor chemokine (C-X-C motif) receptor 3 (CXCR3) which is expressed on activated NK cells and induces NK cell migration toward gradients of the chemokine (C-X-C motif) ligand (CXCL9, 10 and 11). Here, we show that ex vivo expansion of human NK cells results in a tenfold increased expression of the CXCR3 receptor compared with resting NK cells (p = 0.04). Consequently, these NK cells displayed an improved migratory capacity toward solid tumors, which was dependent on tumor-derived CXCL10. In xenograft models, adoptively transferred NK cells showed increased migration toward CXCL10-transfected melanoma tumors compared with CXCL10-negative wild-type tumors, resulting in significantly reduced tumor burden and increased survival (median survival 41 vs. 32 days, p = 0.03). Furthermore, administration of interferon-gamma locally in the tumor stimulated the production of CXCL10 in subcutaneous melanoma tumors resulting in increased infiltration of adoptively transferred CXCR3-positive expanded NK cells. Our findings demonstrate the importance of CXCL10-induced chemoattraction in the anti-tumor response of adoptively transferred expanded NK cells against solid melanoma tumors.
Asunto(s)
Quimiocina CXCL10/inmunología , Inmunoterapia Adoptiva , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Traslado Adoptivo , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Movimiento Celular , Quimiocina CXCL10/metabolismo , Quimiocinas CXC/inmunología , Quimiotaxis de Leucocito/efectos de los fármacos , Quimiotaxis de Leucocito/inmunología , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Humanos , Interferón gamma/administración & dosificación , Interferón gamma/metabolismo , Interferón gamma/farmacología , Células Asesinas Naturales/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/metabolismo , Neoplasias/mortalidad , Neoplasias/patología , Receptores CXCR3/metabolismo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pharmacologic manipulation of the immune system is emerging as a viable and robust treatment for some cancer patients. Exercise-induced modulation of the immune system may be another adjunctive strategy for inhibiting tumor initiation and progression. In healthy individuals, exercise has been shown to modulate a number of cell subsets involved in innate and adaptive immunity. Here, we provide an overview of the current state of knowledge pertaining to exercise modulation of the inflammation-immune axis in cancer. The current evidence suggests that exercise may be a promising adjunctive strategy that can favorably alter numerous components of the immune system, which, in turn, may modulate tumorigenesis. However, many important knowledge gaps are evident. To this end, we propose a framework to guide future research efforts investigating the immune effects of exercise in cancer.
Asunto(s)
Transformación Celular Neoplásica/inmunología , Ejercicio Físico/fisiología , Inflamación/inmunología , Neoplasias/inmunología , Animales , Progresión de la Enfermedad , HumanosRESUMEN
Natural killer (NK) cells are innate lymphocytes that are able to directly kill tumor cells through different mechanisms including ligation of TNF-related apoptosis-inducing ligand (TRAIL) receptors. Zoledronic acid (ZA) is a bisphosphonate known to upregulate the expression of TRAIL on human γδ T cells. Here, we investigated whether exposure to ZA would upregulate TRAIL expression on human NK cells and augment their cytotoxicity against tumor cells. When cocultured with monocytes, treatment with ZA and IL-2 resulted in a significant upregulation of TRAIL expression on human NK cells (p = 0.002). Consequently, ZA-primed NK cells were significantly more cytotoxic against TRAIL sensitive tumor cells (p < 0.0001). In the presence of ZA and IL-2, monocytes produced high levels of IFN-γ; when cultured in the presence of neutralizing antibodies to IFN-γ, TRAIL expression and TRAIL-mediated cytotoxicity of NK cells were significantly reduced. Furthermore, in tumor-bearing SCID/Beige mice, a significant delayed tumor progression and prolonged survival was observed after infusion of ZA-primed NK cells compared with that observed in mice infused with unprimed NK cells. These findings represent a novel approach to potentiate TRAIL-mediated apoptosis by adoptively infused NK cells that could improve the outcome in patients with cancer.
Asunto(s)
Citotoxicidad Inmunológica , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Monocitos/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Animales , Células Cultivadas , Técnicas de Cocultivo , Difosfonatos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Imidazoles/farmacología , Interleucina-2/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/trasplante , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones SCID , Neoplasias/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido ZoledrónicoRESUMEN
Overexpression of the receptor tyrosine kinases HER2 and HER3 is associated with a poor prognosis in several types of cancer. Presently, HER2- as well as HER3-targeted therapies are in clinical practice or evaluated within clinical trials, including treatment with mAbs mediating growth inhibition and/or activation of Ab-induced innate or adaptive cellular immunity. A better understanding of how HER2/HER3 signaling in tumors influences cellular immune mechanisms is therefore warranted. In this study, we demonstrate that HER2/HER3 signaling regulates the expression of MHC class I-related chain A and B (MICA and MICB) in breast cancer cell lines. The MICA and MICB (MICA/B) molecules act as key ligands for the activating receptor NK group 2, member D (NKG2D) and promote NK cell-mediated recognition and cytolysis. Genetic silencing of HER3 but not HER2 downregulated the expression of MICA/B, and HER3 overexpression significantly enhanced MICA expression. Among the major pathways activated by HER2/HER3 signaling, the PI3K/AKT pathway was shown to predominantly regulate MICA/B expression. Treatment with the HER3-specific ligand neuregulin 1ß promoted the expression in a process that was antagonized by pharmacological and genetic interference with HER3 but not by the ataxia-telangiectasia-mutated (ATM) and ATM and Rad3-related protein kinases inhibitor caffeine. These observations further emphasize that HER2/HER3 signaling directly, and not via genotoxic stress, regulates MICA/B expression. As anticipated, stimulating HER2/HER3 enhanced the NKG2D-MICA/B-dependent NK cell-mediated cytotoxicity. Taken together, we conclude that signaling via the HER2/HER3 pathway in breast carcinoma cell lines may lead to enhanced NKG2D-MICA/B recognition by NK cells and T cells.
Asunto(s)
Neoplasias de la Mama/inmunología , Pruebas Inmunológicas de Citotoxicidad , Antígenos de Histocompatibilidad Clase I/biosíntesis , Células Asesinas Naturales/inmunología , Receptor ErbB-2/fisiología , Receptor ErbB-3/fisiología , Transducción de Señal/inmunología , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Línea Celular Tumoral , Pruebas Inmunológicas de Citotoxicidad/métodos , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Sistema de Señalización de MAP Quinasas/inmunología , Receptor ErbB-2/biosíntesis , Receptor ErbB-3/biosíntesis , Transducción de Señal/genética , Subgrupos de Linfocitos T/enzimología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Escape del Tumor/genéticaRESUMEN
PURPOSE: Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials. METHODS AND MATERIALS: We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes. RESULTS: Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART. CONCLUSIONS: This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials.
RESUMEN
Doxorubicin (DOX) is an anthracycline antibiotic that is widely used to treat different types of malignancy. In this study, it was studied whether DOX could be used to render tumor cells susceptible to apoptosis by NK and T cells. Pretreatment with subapoptotic doses of DOX sensitized tumor cell lines of various histotypes to both NK and T cells resulting in a 3.7 to 32.7% increase in lysis (2.5 mean fold increase, p < 0.0001) and a 2.9 to 14.2% increase in lysis (3.0 mean-fold increase, p < 0.05), respectively. The sensitizing effect of the drug was primarily dependent on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptor signaling, but not on Fas-ligand, perforin, NKG2D or DNAM-1. The central role of the TRAIL signaling pathway was further supported by an increased expression of TRAIL-R2 on DOX-treated tumor cells and by downregulation of cellular FLICE inhibitory protein, the inhibitors of death receptor-mediated apoptosis. Compared to untreated cells, pretreatment of tumor cells with DOX showed increased processing and activation of caspase-8 on coculture with NK or T cells. The significance of this treatment strategy was confirmed using a xenogeneic tumor-bearing mouse model. Tumor progression was delayed in mice that received either NK cells (p < 0.05) or T cells (p < 0.0001) following DOX treatment compared to mice receiving either cell type alone. Moreover, combined infusion of both NK and T cells following DOX treatment not only delayed tumor progression but also significantly improved the long-term survival (p < 0.01). Based on these findings, it was proposed that DOX can be used to improve the efficacy of adoptive cell therapy in patients with cancer.
Asunto(s)
Doxorrubicina/farmacología , Células Asesinas Naturales/inmunología , Melanoma/tratamiento farmacológico , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Linfocitos T/inmunología , Animales , Antibióticos Antineoplásicos/farmacología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Apoptosis/efectos de los fármacos , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/biosíntesis , Caspasa 8/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo , Activación Enzimática , Proteína Ligando Fas/metabolismo , Humanos , Inmunoterapia Adoptiva , Melanoma/inmunología , Ratones , Ratones SCID , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Perforina/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Transducción de Señal , Trasplante Heterólogo , Regulación hacia ArribaRESUMEN
The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p < 0.0002) and T cell (p = 0.02)-mediated cytotoxicity. Treatment with b-AP15 resulted in increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 expression (p = 0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p = 0.006), T cells (p < 0.0001) or b-AP15 alone (p = 0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p ≤ 0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer.
Asunto(s)
Apoptosis/inmunología , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Piperidonas/inmunología , Inhibidores de Proteasas/inmunología , Complejo de la Endopetidasa Proteasomal/inmunología , Linfocitos T/inmunología , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Terapia Combinada , Citocinas/inmunología , Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/inmunología , Células HCT116 , Células HeLa , Humanos , Inmunoterapia Adoptiva , Células K562 , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/trasplante , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Neoplasias/patología , Neoplasias/terapia , Piperidonas/farmacología , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Linfocitos T/metabolismo , Linfocitos T/trasplante , Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ubiquitinación/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
Asunto(s)
Neoplasias , Humanos , Neoplasias/terapia , Adenosina , Adenosina Trifosfato , Adenosina Monofosfato , Daño del ADN , Microambiente TumoralRESUMEN
While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central for orchestration of both innate and adaptive immune responses against cancer. The role of P2X7R in anti-tumour immunity is complex and preclinical studies have described opposing roles of the P2X7R in regulating immune responses against tumours. Therefore, few P2X7R modulators have reached clinical testing in cancer patients. Here, we review the prognostic value of P2X7R in cancer, how P2X7R have been targeted to date in tumour models, and we discuss four aspects of how tumours skew immune responses to promote immune escape via the P2X7R; non-pore functional P2X7Rs, mono-ADP-ribosyltransferases, ectonucleotidases, and immunoregulatory cells. Lastly, we discuss alternative approaches to offset tumour immune escape via P2X7R to enhance immunotherapeutic strategies in cancer patients.
Asunto(s)
Neoplasias , Escape del Tumor , Humanos , Receptores Purinérgicos P2X7 , Transducción de SeñalRESUMEN
Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias de la Mama Triple Negativas , Femenino , Animales , Ratones , Humanos , Inmunoterapia , Antígenos CD40 , Terapia Combinada , Neoplasias de la Mama Triple Negativas/radioterapiaRESUMEN
We recently identified the adenosine-5'-diphosphate (ADP)-ribosyltransferase-1 (ART1) as a novel immune checkpoint expressed by cancer cells. ART1 utilizes free nicotinamide adenine dinucleotide (NAD+) in the tumor microenvironment (TME) to mono-ADP-ribosylate (MARylate) the P2X7 receptor (P2X7R) on CD8 T cells, resulting in NAD-induced cell death (NICD) and tumor immune resistance. This process is blocked by therapeutic antibody targeting of ART1.
Asunto(s)
ADP Ribosa Transferasas , NAD , ADP Ribosa Transferasas/metabolismo , Adenosina Difosfato , Muerte Celular , NAD/metabolismo , NAD/farmacología , Escape del TumorRESUMEN
Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.
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Antineoplásicos Inmunológicos , Neoplasias , Antineoplásicos Inmunológicos/efectos adversos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
Most patients with non-small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)-induced cell death (NICD) of P2X7 receptor (P2X7R)-expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono-adenosine 5'-diphosphate (ADP)-ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R+ CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R+ CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD+-degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell-dependent manner. This was associated with increased infiltration of activated P2X7R+CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies.
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ADP Ribosa Transferasas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Subgrupos de Linfocitos T , ADP Ribosa Transferasas/genética , ADP Ribosa Transferasas/metabolismo , Adenosina Difosfato , Animales , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Proteínas Ligadas a GPI/genética , Humanos , Neoplasias Pulmonares/inmunología , RatonesRESUMEN
Accumulating preclinical and clinical evidence indicates that high degrees of heterogeneity among malignant cells constitute a considerable obstacle to the success of cancer therapy. This calls for the development of approaches that operate - or enable established treatments to operate - despite such intratumoral heterogeneity (ITH). In this context, oncolytic peptides stand out as promising therapeutic tools based on their ability to drive immunogenic cell death associated with robust anticancer immune responses independently of ITH. We review the main molecular and immunological pathways engaged by oncolytic peptides, and discuss potential approaches to combine these agents with modern immunotherapeutics in support of superior tumor-targeting immunity and efficacy in patients with cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Muerte Celular Inmunogénica/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Péptidos/farmacología , Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Sinergismo Farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/inmunología , Neoplasias/patología , Péptidos/uso terapéutico , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunologíaRESUMEN
LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumor-targeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners. We found that breast cancer control by LTX-315 is accompanied by a reconfiguration of the immunological tumor microenvironment that supports the activation of anticancer immunity and can be boosted by radiation therapy. Mechanistically, depletion of natural killer (NK) cells compromised the capacity of LTX-315 to limit local and systemic disease progression in a mouse model of triple-negative breast cancer, and to extend the survival of mice bearing hormone-accelerated, carcinogen-driven endogenous mammary carcinomas. Altogether, our data suggest that LTX-315 controls breast cancer progression by engaging NK cell-dependent immunity.
Asunto(s)
Oligopéptidos , Neoplasias de la Mama Triple Negativas , Animales , Humanos , Inmunoterapia , Células Asesinas Naturales , Ratones , Neoplasias de la Mama Triple Negativas/terapia , Microambiente TumoralRESUMEN
Cancer patients with low or absent pre-existing anti-tumour immunity ("cold" tumours) respond poorly to treatment with immune checkpoint inhibitors (ICPI). In order to render these patients susceptible to ICPI, initiation of de novo tumour-targeted immune responses is required. This involves triggering of inflammatory signalling, innate immune activation including recruitment and stimulation of dendritic cells (DCs), and ultimately priming of tumour-specific T cells. The ability of tumour localised therapies to trigger these pathways and act as in situ tumour vaccines is being increasingly explored, with the aspiration of developing combination strategies with ICPI that could generate long-lasting responses. In this effort, it is crucial to consider how therapy-induced changes in the tumour microenvironment (TME) act both as immune stimulants but also, in some cases, exacerbate immune resistance mechanisms. Increasingly refined immune monitoring in pre-clinical studies and analysis of on-treatment biopsies from clinical trials have provided insight into therapy-induced biomarkers of response, as well as actionable targets for optimal synergy between localised therapies and ICB. Here, we review studies on the immunomodulatory effects of novel and experimental localised therapies, as well as the re-evaluation of established therapies, such as radiotherapy, as immune adjuvants with a focus on ICPI combinations.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunomodulación , Inmunoterapia/métodos , Neoplasias/terapia , Adyuvantes Inmunológicos/uso terapéutico , Animales , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/efectos de la radiación , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , Células Dendríticas/inmunología , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Herpesvirus Humano 1/fisiología , Humanos , Inmunidad Innata/efectos de los fármacos , Agentes Inmunomoduladores/uso terapéutico , Inmunomodulación/efectos de los fármacos , Inmunomodulación/efectos de la radiación , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/radioterapia , Viroterapia Oncolítica , Subgrupos de Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Tumor infiltration of conventional dendritic cells has been shown to be essential for triggering efficient antitumor immune responses. These findings have generated an increasing demand for reliable methods to accurately identify and quantify specific DC-subpopulations, both in immune monitoring of clinical trial samples as well as in preclinical mouse tumor models. Here, we describe a flow cytometric approach to assess percentages and absolute counts of conventional dendritic cells in solid mouse tumors.