RESUMO
Cancer immunotherapies have rapidly changed the therapeutic landscape for cancer. Nevertheless, most of the patients show innate or acquired resistance to these therapies. Studies conducted in recent years have highlighted an emerging role of cancer-associated fibroblasts (CAFs) in immune regulation that shapes the tumor immune microenvironment (TIME) and influences response to cancer immunotherapies. In this review, we outline recent advances in the understanding of phenotypic and functional heterogeneity of CAFs. We will focus on emerging roles of CAFs in shaping the TIME, especially under a framework of tumor immunity continuum, and discuss current and future CAF-targeting therapeutic strategies in particular in the context of optimizing the success of immunotherapies.
Assuntos
Fibroblastos Associados a Câncer , Neoplasias , Humanos , Imunoterapia , Neoplasias/terapia , Microambiente TumoralRESUMO
Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi(+) domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)(high) T cell Ig mucin-3(+) CD8(+) T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8(+) T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8(+) T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity.
Assuntos
Adenocarcinoma/terapia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma de Células Renais/terapia , Neoplasias do Colo/terapia , Imunoterapia/métodos , Interleucina-15/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Adenocarcinoma/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Memória Imunológica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacosRESUMO
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
Assuntos
Biomarcadores Tumorais/genética , Fibroblastos/imunologia , Neoplasias Ovarianas/imunologia , Análise de Célula Única/métodos , Células Estromais/imunologia , Linfócitos T/imunologia , Microambiente Tumoral , Biomarcadores Tumorais/imunologia , Quimiocina CXCL12/genética , Quimiocina CXCL12/imunologia , Quimiocina CXCL16/genética , Quimiocina CXCL16/imunologia , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA-Seq , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Receptores CXCR6/genética , Receptores CXCR6/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
BACKGROUND: Oxazaphosphorines (cyclophosphamide (CPA), ifosfamide (IFO)) are major alkylating agents of polychemotherapy protocols but limiting their toxicity and increasing their efficacy could be of major interest. Oxazaphosphorines are prodrugs that require an activation by cytochrome P450 (CYP). CPA is mainly metabolized (>80%) to phosphoramide mustard while only 10%-50% of IFO is transformed in the alkylating entity, isophosphoramide mustard and 50%-90% of IFO release chloroacetaldehyde, a nephrotoxic and neurotoxic metabolite. Geranyloxy-IFO (G-IFO) was reported as a preactivated IFO to circumvent the toxic pathway giving directly the isophosphoramide mustard without CYP metabolization. The similarity in structure of CPA and IFO and the similarity in metabolic balance of CPA and G-IFO have led us to explore immunomodulatory effect of these components in mice and to investigate the combination of these oxazaphosphorines with immune checkpoint blockers (ICB). METHODS: The investigation of the immunomodulatory properties of IFO and G-IFO compared with CPA has been conducted through immune cell phenotyping by flow cytometry and analysis of the cytokine profile of T cells after ex-vivo restimulation. T cell-mediated antitumor efficacy was confirmed in CD4+ and CD8+ T cell-depleted mice. A combination of oxazaphosphorines with an anti-programmed cell death 1 (PD-1) antibody has been studied in MCA205 tumor-bearing mice. RESULTS: Studies on a MCA205 mouse model have demonstrated a dose-dependent effect of IFO and G-IFO on T cell immunity. These components in particular favored Th1 polarization when used at low dose (150 and eq. 100 mg/kg, respectively). Antitumor activity at low dose was abolished in mice depleted in CD4+ and CD8+ T cells. G-IFO at low dose (eq. 100 mg/kg) in combination with anti-PD-1 antidody showed high synergistic antitumor efficacy compared with IFO. CONCLUSION: Oxazaphosphorines are characterized by a dual mechanism of antitumor action; low-dose schedules should be preferred in combination with ICB, and dose escalation was found to have better utility in polychemotherapy protocols where a conventional direct cytotoxic anticancer effect is needed. G-IFO, the novel oxazaphosphorine drug, has shown a better metabolic index compared with IFO as its metabolization gives mainly the alkylating mustard as CPA (and not IFO) and a best potential in combination with ICB.
Assuntos
Antineoplásicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Mostardas de Fosforamida/uso terapêutico , Animais , Antineoplásicos/farmacologia , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Mostardas de Fosforamida/farmacologiaRESUMO
BACKGROUND: As the immune system is compromised in patients with cancer, therapeutic strategies to stimulate immunity appear promising, to avoid relapse and increase long-term overall survival. Interleukin-15 (IL-15) has similar properties to IL-2, but does not cause activation-induced cell death nor activation and proliferation of regulatory T cells (Treg), which makes it a serious candidate for anticancer immunotherapy. However, IL-15 has a short half-life and high doses are needed to achieve responses. Designed to enhance its activity, receptor-linker-IL-15 (RLI) (SO-C101) is a fusion molecule of human IL-15 covalently linked to the human IL-15Rα sushi+ domain currently assessed in a phase I/Ib clinical trial on patients with advanced/metastatic solid cancer. METHODS: We investigated the antimetastatic activity of RLI in a 4T1 mouse mammary carcinoma that spontaneously metastasizes and evaluated its immunomodulatory role in the metastatic lung microenvironment. We further characterized the proliferation, maturation and cytotoxic functions of natural killer (NK) cells in tumor-free mice treated with RLI. Finally, we explored the effect of RLI on human NK cells from healthy donors and patients with non-small cell lung cancer (NSCLC). RESULTS: RLI treatment displayed antimetastatic properties in the 4T1 mouse model. By characterizing the lung microenvironment, we observed that RLI restored the balance between NK cells and neutrophils (CD11b+ Ly6Ghigh Ly6Clow) that massively infiltrate lungs of 4T1-tumor bearing mice. In addition, the ratio between NK cells and Treg was strongly increased by RLI treatment. Further pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ mature NK cells. Finally, RLI demonstrated potent immunostimulatory properties on human NK cells by inducing proliferation and activation of NK cells from healthy donors and enhancing cytotoxic responses to NKp30 crosslinking in NK cells from patients with NSCLC. CONCLUSIONS: Collectively, our work demonstrates superior activity of RLI compared with rhIL-15 in modulating and activating NK cells and provides additional evidences for a therapeutic strategy using RLI as antimetastatic molecule.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Interleucina-15/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Linhagem Celular Tumoral/transplante , Feminino , Voluntários Saudáveis , Humanos , Interleucina-15/agonistas , Células Matadoras Naturais/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Cultura Primária de Células , Proteínas Recombinantes/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFß and activated stroma. Furthermore, we identify TGFß as an important mediator of T cell exclusion. TGFß reduces MHC-I expression in ovarian cancer cells in vitro. TGFß also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFß might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Epitelial do Ovário/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Ovarianas/imunologia , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral/imunologia , Apresentação de Antígeno/imunologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Metilação de DNA , Endopeptidases , Feminino , Gelatinases/metabolismo , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Aprendizado de Máquina , Proteínas de Membrana/metabolismo , Família Multigênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , RNA-Seq , Serina Endopeptidases/metabolismo , Células Estromais/metabolismoRESUMO
Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
Assuntos
Biomarcadores Tumorais/sangue , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Ácidos Graxos Voláteis/sangue , Neoplasias/sangue , Neoplasias/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Biomarcadores Tumorais/metabolismo , Butiratos/sangue , Células Dendríticas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Humanos , Ipilimumab/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Propionatos/sangue , RNA Ribossômico 16S/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
The discovery and understanding of complex cellular interactions that govern the immune system contributed to the pharmacological targeting of anti-tumor immunity. The activity of immune effector cells, such as NK and T-cells, is regulated by a wide range of activating and inhibiting receptors or ligands. Drugs that target these receptors or ligands can modulate the immune response by exerting antagonistic or agonistic effects. Over the past decade, several immunomodulators have demonstrated clinical effectiveness, and three of them have already been approved for use in oncology. The development of these immunotherapy approaches presented unique challenges for safety and efficacy, requiring revising clinical response criteria and the establishment of guidelines to help oncologists to manage properly inflammatory toxicities. The introduction of these immunotherapies is a revolution in oncology. However, additional efforts in terms of optimizing treatment administration and identification of biomarkers are needed. Identifying the immunodynamics of various immunomodulators should allow a better understanding of anti-tumor and inflammatory mechanisms, and certainly give the opportunity to develop effective therapeutic combinations without potentiating adverse events.
Assuntos
Tolerância Imunológica , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Neoplasias/imunologia , Antígeno CTLA-4/imunologia , Humanos , Indóis/uso terapêutico , Ipilimumab , Células Matadoras Naturais/fisiologia , Melanoma/imunologia , Melanoma/terapia , Nivolumabe , Sulfonamidas/uso terapêutico , Linfócitos T/fisiologia , Microambiente Tumoral/imunologia , VemurafenibRESUMO
The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and ß subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.
Assuntos
Antígeno CTLA-4/metabolismo , Subunidade alfa de Receptor de Interleucina-2/sangue , Melanoma/patologia , Receptores de Interleucina-2/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/imunologia , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Ipilimumab , Masculino , Melanoma/mortalidade , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Linfócitos T Reguladores/imunologia , Regulação para Cima/efeitos dos fármacos , Adulto JovemRESUMO
We performed a Phase I clinical trial from October 2007 to October 2009, enrolling patients affected by refractory solid tumors, to determine the maximum tolerated dose (MTD) of interleukin (IL)-2 combined with low dose cyclophosphamide (CTX) and imatinib mesylate (IM). In a companion paper published in this issue of OncoImmunology, we show that the MTD of IL-2 is 6 MIU/day for 5 consecutive days, and that IL-2 increases the impregnation of both IM and of its main metabolite, CGP74588. Among the secondary objectives, we wanted to determine immunological markers that might be associated with progression-free survival (PFS) and/or overall survival (OS). The combination therapy markedly reduced the absolute counts of B, CD4+ T and CD8+ T cells in a manner that was proportional to IL-2 dose. There was a slight (less than 2-fold) increase in the proportion of regulatory T cells (Tregs) among CD4+ T cells in response to IM plus IL-2. The natural killer (NK)-cell compartment was activated, exhibiting a significant upregulation of HLA-DR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD56. The abundance of HLA-DR+ NK cells after one course of combination therapy positively correlated with both PFS and OS. The IL-2-induced rise of the CD4+:CD8+ T-cell ratio calculated after the first cycle of treatment was also positively associated with OS. Overall, the combination of IM and IL-2 promoted the rapid expansion of HLA-DR+ NK cells and increased the CD4+:CD8+ T-cell ratio, both being associated with clinical benefits. This combinatorial regimen warrants further investigation in Phase II clinical trials, possibly in patients affected by gastrointestinal stromal tumors, a setting in which T and NK cells may play an important therapeutic role.
RESUMO
Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3(+) TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3(+) TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56(bright) (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST.
Assuntos
Tumores do Estroma Gastrointestinal/imunologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas/imunologia , Benzamidas/uso terapêutico , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Estudos de Coortes , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Mesilato de Imatinib , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Piperazinas/imunologia , Piperazinas/uso terapêutico , Prognóstico , Inibidores de Proteínas Quinases/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/imunologia , Pirimidinas/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Resultado do TratamentoRESUMO
Natural killer (NK) cells belong to the innate immune system and were initially described functionallywise by their spontaneous cytotoxic potential against transformed or virus-infected cells. A delicate balance between activating and inhibiting receptors regulates NK cell tolerance. A better understanding of tissue resident NK cells, of NK cell maturation stages and migration patterns has evolved allowing a thoughtful evaluation of their modus operandi. While evidence has been brought up for their relevance as gate keepers in some hematopoietic malignancies, the role of NK cells against progression and dissemination of solid tumors remains questionable. Hence, many studies pointed out the functional defects of the rare NK cell infiltrates found in tumor beds and the lack of efficacy of adoptively transferred NK cells in patients. However, several preclinical evidences suggest their anti-metastatic role in a variety of mouse tumor models. In the present review, we discuss NK cell functions according to their maturation stage and environmental milieu, the receptor/ligand interactions dictating tumor cell recognition and recapitulate translational studies aimed at deciphering their prognostic or predictive role against human solid malignancies.
RESUMO
During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1-dependent tumor progression in NK cell-controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit(-) (CD11b(-)) into Kit(+) natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit(+) NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit(+) NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1-dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18-binding protein dramatically reduced the accumulation of Kit(+)CD11b(-) NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit(+)CD11b(-) NK cells endowed with B7-H1-dependent immunoablative functions in mice.
Assuntos
Interleucina-18/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Animais , Antígeno B7-H1/análise , Antígeno B7-H1/fisiologia , Antígeno CD11b/análise , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-kit/análiseRESUMO
Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18.