RESUMEN
Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy.
Asunto(s)
Antígenos de Neoplasias , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Melanoma , Factores de Transcripción , Vemurafenib , Animales , Humanos , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Ratones , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Resistencia a Antineoplásicos/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Inmunoterapia/métodos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/inmunología , Línea Celular Tumoral , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación , Terapia Molecular Dirigida/métodos , Ratones Endogámicos C57BLRESUMEN
The use of antitumor drugs represents a reliable strategy for cancer therapy. Unfortunately, drug resistance has become increasingly common and contributes to tumor metastasis and local recurrence. The tumor immune microenvironment (TME) consists of immune cells, cytokines and immunomodulators, and collectively they influence the response to treatment. Epigenetic changes including DNA methylation and histone modification, as well as increased drug exportation have been reported to contribute to the development of drug resistance in cancers. In the past few years, the majority of studies on tumors have only focused on the development and progression of a tumor from a mechanistic standpoint; few studies have examined whether the changes in the TME can also affect tumor growth and drug resistance. Recently, emerging evidence have raised more concerns regarding the role of TME in the development of drug resistance. In the present review, it was discussed how the suppressive TME adapts to drug resistance characterized by the cooperation of immune cells, cytokines, immunomodulators, stromal cells and extracellular matrix. Furthermore, it was reviewed how these immunological or metabolic changes alter immunosurveillance and thus facilitate tumor drug resistance. In addition, potential targets present in the TME for developing novel therapeutic strategies to improve individualized therapy for cancer treatment were revealed.
Asunto(s)
Resistencia a Antineoplásicos , Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Epigénesis Genética/efectos de los fármacos , Animales , Citocinas/metabolismoRESUMEN
The clinical response to immune checkpoint inhibitors may vary by tumor type and many tumors present with either primary or acquired resistance to immunotherapy. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. This is increasingly important for tumors with primary resistance as effective biomarkers in this setting can guide clinicians about appropriate treatment regimen selection in the first-line setting. Multiple potential biological mechanisms of primary resistance have been proposed but most are yet to be validated in prospective clinical cohorts. Individual biomarkers have poor specificity and sensitivity, and the development of validated and integrated predictive models may guide which patient will benefit from monotherapy versus combination therapy. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these.
Asunto(s)
Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/terapia , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Genómica/métodos , Biomarcadores de Tumor/genética , Inmunoterapia/métodos , AnimalesRESUMEN
Despite advances in cancer treatment, pancreatic cancer (PC) remains a disease with high mortality rates and poor survival outcomes. The B7 homolog 3 (B7-H3) checkpoint molecule is overexpressed among many malignant tumors, including PC, with low or absent expression in healthy tissues. By modulating various immunological and nonimmunological molecular mechanisms, B7-H3 may influence the progression of PC. However, the impact of B7-H3 on the survival of patients with PC remains a subject of debate. Still, most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC. Furthermore, it has been demonstrated that B7-H3 stimulates the migration, invasion, and metastasis of PC cells, and enhances resistance to chemotherapy. In preclinical models of PC, B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibody-dependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site. Finally, PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies. This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.
Asunto(s)
Antígenos B7 , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Antígenos B7/metabolismo , Antígenos B7/antagonistas & inhibidores , Antígenos B7/inmunología , Animales , Resistencia a Antineoplásicos/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Antineoplásicos Inmunológicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers. Preclinical studies and mouse models suggest that therapies targeting CD276 may outperform PD1/PD-L1 blockade. However, data from mouse models indicate a significant non-responsive population to anti-CD276 treatment, with the mechanisms of resistance still unclear. In this study, we evaluate the activity of anti-CD276 antibodies in a chemically-induced murine model of head and neck squamous cell carcinoma. Using models of induced and orthotopic carcinogenesis, we identify ITGB6 as a key gene mediating differential responses to anti-CD276 treatment. Through single-cell RNA sequencing and gene-knockout mouse models, we find that ITGB6 regulates the expression of the tumor-associated chemokine CX3CL1, which recruits and activates PF4+ macrophages that express high levels of CX3CR1. Inhibition of the CX3CL1-CX3CR1 axis suppresses the infiltration and secretion of CXCL16 by PF4+ macrophages, thereby reinvigorating cytotoxic CXCR6+ CD8+ T cells and enhancing sensitivity to anti-CD276 treatment. Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.
Asunto(s)
Antígenos B7 , Neoplasias de Cabeza y Cuello , Ratones Noqueados , Animales , Ratones , Antígenos B7/metabolismo , Antígenos B7/genética , Antígenos B7/antagonistas & inhibidores , Humanos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Receptor 1 de Quimiocinas CX3C/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Línea Celular Tumoral , Ratones Endogámicos C57BL , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Modelos Animales de Enfermedad , Femenino , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Tumor resistance poses a significant challenge to effective cancer treatment, making it imperative to explore new therapeutic strategies. Recent studies have highlighted the profound involvement of immune cells in the development of tumor resistance. Within the tumor microenvironment, macrophages undergo polarization into the M2 phenotype, thus promoting the emergence of drug-resistant tumors. Neutrophils contribute to tumor resistance by forming extracellular traps. While T cells and natural killer (NK) cells exert their impact through direct cytotoxicity against tumor cells. Additionally, dendritic cells (DCs) have been implicated in preventing tumor drug resistance by stimulating T cell activation. In this review, we provide a comprehensive summary of the current knowledge regarding immune cell-mediated modulation of tumor resistance at the molecular level, with a particular focus on macrophages, neutrophils, DCs, T cells, and NK cells. The targeting of immune cell modulation exhibits considerable potential for addressing drug resistance, and an in-depth understanding of the molecular interactions between immune cells and tumor cells holds promise for the development of innovative therapies. Furthermore, we explore the clinical implications of these immune cells in the treatment of drug-resistant tumors. This review emphasizes the exploration of novel approaches that harness the functional capabilities of immune cells to effectively overcome drug-resistant tumors.
Asunto(s)
Células Dendríticas , Resistencia a Antineoplásicos , Células Asesinas Naturales , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Resistencia a Antineoplásicos/inmunología , Microambiente Tumoral/inmunología , Células Asesinas Naturales/inmunología , Células Dendríticas/inmunología , Linfocitos T/inmunología , Animales , Macrófagos/inmunología , Neutrófilos/inmunologíaRESUMEN
Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.
Asunto(s)
Resistencia a Antineoplásicos , Inmunoterapia , Uridina Difosfato , Humanos , Uridina Difosfato/metabolismo , Inmunoterapia/métodos , Resistencia a Antineoplásicos/inmunología , Animales , Ratones , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/tratamiento farmacológico , Citidina Desaminasa/metabolismo , Citidina Desaminasa/genética , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Línea Celular Tumoral , Receptores Purinérgicos P2/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Microambiente Tumoral/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Nucleótidos/metabolismo , Tolerancia Inmunológica , Receptor de Muerte Celular Programada 1RESUMEN
BACKGROUND: Lung cancer is the primary cause of cancer-related deaths, with one of the highest incidence and mortality rates of all malignant tumors. Dysregulated expression of DEPDC1B has been reported to occur in various tumor types. However, the functional implications of this alteration in lung adenocarcinoma (LUAD) and the underlying molecular mechanism remains unclear. In this study, we investigated the role and clinical significance of DEPDC1B in LUAD. METHODS: The expression of DEPDC1B in LUAD and its relationship with prognosis were systematically evaluated in several publically available datasets. The effects of DEPDC1B knockdown on the proliferation and motility of LUAD cells were assessed using the JULI Stage Real-time Cell History Recorder, while the effect of knockdown on the cell cycle was studied by flow cytometry. Furthermore, RNA-Sequencing (RNA-Seq) analysis was conducted to identify the downstream target genes and pathways regulated by DEPDC1B. Correlations between the expression of DEPDC1B and immune cell infiltration, immunotherapy resistance, and chemoresistance were also examined. Additionally, molecular biological methods were used to explore the regulatory mechanism of B-Myb on DEPDC1B expression. RESULTS: DEPDC1B was found to be upregulated in LUAD patients and this was associated with poor clinical outcomes. Knockdown of DEPDC1B inhibited cell growth, migration and motility, as well as cell cycle progression. Knockdown also resulted in the down-regulation of several downstream genes, including NID1, FN1, and EGFR, as well as the inactivation of multiple critical pathways, such as the ERK and PI3K-AKT pathways. Analysis of the tumor immuno-environment in LUAD revealed that high DEPDC1B expression was associated with an abundance of activated CD4+ memory T cells, M0 macrophages, M1 macrophages, and CD8+ T cells. Moreover, these tumors responded poorly to immunotherapy. Analysis of chemo-drug sensitivity showed that LUADs with high DEPDC1B expression were more responsive to frontline chemotherapeutic drugs such as Vinorelbine, Cisplatin, and Etoposide. Additionally, mechanistic investigations revealed that DEPDC1B is a direct target gene of B-Myb, and that its knockdown attenuated the proliferation and motility effects of B-Myb. CONCLUSIONS: In summary, our findings indicate that DEPDC1B is a critical regulator during the malignant progression of LUAD. DEPDC1B could therefore be a promising prognostic marker and therapeutic target in LUAD diagnosis and treatment.
Asunto(s)
Adenocarcinoma del Pulmón , Movimiento Celular , Proliferación Celular , Proteínas Activadoras de GTPasa , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Proliferación Celular/genética , Movimiento Celular/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Pronóstico , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Masculino , Técnicas de Silenciamiento del Gen , Transducción de Señal , Proteínas de Neoplasias , TransactivadoresRESUMEN
The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular immune-checkpoint inhibitors (ICIs). These immunotherapies release the host's immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable, such as metastatic melanoma, metastatic renal cell carcinoma (RCC), microsatellite instability (MSI) high colorectal cancer and late stages of non-small cell lung cancer (NSCLC). However, about 80% of the patients fail to respond to these immunotherapies and are therefore left with other less effective and potentially toxic treatments. Identifying and understanding the mechanisms that enable cancerous cells to adapt to and eventually overcome therapy can help circumvent resistance and improve treatment. In this review, we describe the recent discoveries on the onco-immunological processes which govern the tumor microenvironment and their impact on the resistance to PD-1/PD-L1 checkpoint blockade.
Asunto(s)
Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Microambiente Tumoral , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Resistencia a Antineoplásicos/inmunología , Microambiente Tumoral/inmunología , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Animales , Inmunoterapia/métodos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
Asunto(s)
Resistencia a Antineoplásicos , Evasión Inmune , Neoplasias , Células Madre Neoplásicas , Humanos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/patología , Resistencia a Antineoplásicos/inmunología , Animales , Inmunoterapia/métodosRESUMEN
Recent studies have utilized evolutionary mechanisms to impede the emergence of drug-resistant populations. In this paper, we develop a mathematical model that integrates hormonal treatment, immunotherapy, and the interactions among three cell types: drug-sensitive cancer cells, drug-resistant cancer cells and immune effector cells. Dynamical analysis is performed, examining the existence and stability of equilibria, thereby confirming the model's interpretability. Model parameters are calibrated using available prostate cancer data and literature. Through bifurcation analysis for drug sensitivity under different immune effector cells recruitment responses, we find that resistant cancer cells grow rapidly under weak recruitment response, maintain at a low level under strong recruitment response, and both may occur under moderate recruitment response. To quantify the competitiveness of sensitive and resistant cells, we introduce the comprehensive measures R1 and R2, respectively, which determine the outcome of competition. Additionally, we introduce the quantitative indicators CIE1 and CIE2 as comprehensive measures of the immune effects on sensitive and resistant cancer cells, respectively. These two indicators determine whether the corresponding cancer cells can maintain at a low level. Our work shows that the immune system is an important factor affecting the evolution of drug resistance and provides insights into how to enhance immune response to control resistance.
Asunto(s)
Resistencia a Antineoplásicos , Humanos , Resistencia a Antineoplásicos/inmunología , Masculino , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/tratamiento farmacológico , Modelos Biológicos , Inmunoterapia/métodos , Dinámicas no Lineales , Conceptos MatemáticosRESUMEN
Immunotherapies have revolutionized the treatment of certain cancers, but challenges remain in overcoming immunotherapy resistance. Research shows that metabolic modulation of the tumor microenvironment can enhance antitumor immunity. Here, we discuss recent preclinical and clinical evidence for the efficacy of combining metabolic modifiers with immunotherapies. While this combination holds great promise, a few key areas must be addressed, which include identifying the effects of metabolic modifiers on immune cell metabolism, the putative biomarkers of therapeutic efficacy, the efficacy of modifiers on tumors harboring metabolic heterogeneity, and the potential development of resistance due to tumor reliance on alternative metabolic pathways. We propose solutions to these problems and posit that assessing these parameters is crucial for considering the potential of metabolic modifiers in sensitizing tumors to immunotherapies.
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Resistencia a Antineoplásicos , Inmunoterapia , Redes y Vías Metabólicas , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Animales , Resistencia a Antineoplásicos/inmunologíaRESUMEN
Cervical cancer affects thousands of women globally with recurring high-risk HPV infections being at the centre of cervical pathology. Oncological treatment strategies are continually challenged by both chemoresistance and metastasis within patients. Although both work hand-in-hand, targeting their individual mechanisms could prove highly beneficial for treatment outcomes. Such targets include the metastatic-promoting stem cell marker, CD44, which is abundant in cervical cancer cells and is common to both chemoresistance and metastatic mechanisms. Seeing that many existing advanced-stage cervical cancer treatment regimes, such as platinum-based chemotherapy regimens, remain limited and are rarely curative, alternative treatment options within the field of immunology are being considered. The use of immune checkpoint inhibition therapy, which targets immune checkpoints, CTLA-4 and PD-1/PD-L1, has shown promise as an alternate standard of care for patients suffering from advanced-stage cervical cancer. Therefore, this review aims to assess whether immune checkpoint inhibition can mitigate the pathological effects of CD44-induced EMT, metastasis, and chemoresistance in cervical cancer patients.
Asunto(s)
Resistencia a Antineoplásicos , Receptores de Hialuranos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Receptores de Hialuranos/metabolismo , Femenino , Resistencia a Antineoplásicos/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Metástasis de la Neoplasia , Progresión de la Enfermedad , Animales , Transición Epitelial-Mesenquimal/inmunologíaRESUMEN
Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.
Asunto(s)
Carcinoma Ductal Pancreático , Resistencia a Antineoplásicos , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Resistencia a Antineoplásicos/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Animales , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Tolerancia InmunológicaRESUMEN
Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.
Asunto(s)
Inmunoterapia , Células Supresoras de Origen Mieloide , Neoplasias , Linfocitos T Reguladores , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Linfocitos T Reguladores/inmunología , Células Supresoras de Origen Mieloide/inmunología , Escape del Tumor/inmunología , Resistencia a Antineoplásicos/inmunología , Animales , Terapia de InmunosupresiónRESUMEN
In the tumor microenvironment (TME), myeloid cells play a pivotal role. Myeloid-derived immunosuppressive cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), are central components in shaping the immunosuppressive milieu of the tumor. Within the TME, a majority of TAMs assume an M2 phenotype, characterized by their pro-tumoral activity. These cells promote tumor cell growth, angiogenesis, invasion, and migration. In contrast, M1 macrophages, under appropriate activation conditions, exhibit cytotoxic capabilities against cancer cells. However, an excessive M1 response may lead to pro-tumoral inflammation. As a result, myeloid cells have emerged as crucial targets in cancer therapy. This review concentrates on gastrointestinal tumors, detailing methods for targeting macrophages to enhance tumor radiotherapy and immunotherapy sensitivity. We specifically delve into monocytes and tumor-associated macrophages' various functions, establishing an immunosuppressive microenvironment, promoting tumorigenic inflammation, and fostering neovascularization and stromal remodeling. Additionally, we examine combination therapeutic strategies.
Asunto(s)
Resistencia a Antineoplásicos , Neoplasias Gastrointestinales , Microambiente Tumoral , Humanos , Neoplasias Gastrointestinales/terapia , Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Resistencia a Antineoplásicos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Animales , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Células Mieloides/inmunología , Células Mieloides/efectos de los fármacos , Inmunoterapia/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodosRESUMEN
PURPOSE: Bispecific antibodies (BsAb) directed against B-cell maturation antigen (teclistamab) or the orphan G protein-coupled receptor GPRC5D (talquetamab) induce deep and durable responses in heavily pretreated patients with multiple myeloma. However, mechanisms underlying primary and acquired resistance remain poorly understood. EXPERIMENTAL DESIGN: The anti-multiple myeloma activity of teclistamab and talquetamab was evaluated in bone marrow (BM) samples from patients with multiple myeloma. T-cell phenotype and function were assessed in BM/peripheral blood samples obtained from patients with multiple myeloma who were treated with these BsAb. RESULTS: In ex vivo killing assays with 41 BM samples from BsAb-naive patients with multiple myeloma, teclistamab- and talquetamab-mediated multiple myeloma lysis was strongly correlated (r = 0.73, P < 0.0001). Both BsAb exhibited poor activity in samples with high regulatory T-cell (Treg) numbers and a low T-cell/multiple myeloma cell ratio. Furthermore, comprehensive phenotyping of BM samples derived from patients treated with teclistamab or talquetamab revealed that high frequencies of PD-1+ CD4+ T cells, CTLA4+ CD4+ T cells, and CD38+ CD4+ T cells were associated with primary resistance. Although this lack of response was linked to a modest increase in the expression of inhibitory receptors, increasing T-cell/multiple myeloma cell ratios by adding extra T cells enhanced sensitivity to BsAb. Further, treatment with BsAb resulted in an increased proportion of T cells expressing exhaustion markers (PD-1, TIGIT, and TIM-3), which was accompanied by reduced T-cell proliferative potential and cytokine secretion, as well as impaired antitumor efficacy in ex vivo experiments. CONCLUSIONS: Primary resistance is characterized by a low T-cell/multiple myeloma cell ratio and Treg-driven immunosuppression, whereas reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to the development of acquired resistance.
Asunto(s)
Anticuerpos Biespecíficos , Resistencia a Antineoplásicos , Mieloma Múltiple , Mieloma Múltiple/inmunología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Humanos , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Resistencia a Antineoplásicos/inmunología , Antígeno de Maduración de Linfocitos B/inmunología , Linfocitos T Reguladores/inmunología , Femenino , Masculino , Linfocitos T/inmunología , Linfocitos T/metabolismo , Persona de Mediana Edad , Anciano , Receptores Acoplados a Proteínas GRESUMEN
Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.
Asunto(s)
Anticuerpos Biespecíficos , Linfoma de Células B Grandes Difuso , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/farmacología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Resistencia a Antineoplásicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Epithelial ovarian cancer (OC) is the deadliest female reproductive cancer; an estimated 13,270 women will die from OC in 2023. Platinum-based chemotherapy resistance mechanisms contribute to poor OC 5-year survival rates. Peripheral inflammation is linked to various disease states and we previously identified unique peritoneal microbial features predictive of OC. We hypothesized that unique peripheral immune profiles and peritoneal microbial features may be predictive of disease-free interval (time to recurrence) and response to chemotherapy in participants with OC. We also investigated self-rated health (SRH) scores in the context of peripheral inflammation as a potential screening tool for OC. Blood and peritoneal fluid were collected from participants with OC or a benign adnexal mass (BPM). Lymphocyte populations were analyzed using Fluorescence Activated Cell Sorting, serum cytokine levels were analyzed using the Human Th17 Magnetic Bead Panel assay and peritoneal fluid microbial features were analyzed using Next Generation Sequencing (NGS). Participants completed a standardized questionnaire on self-rated physical and emotional health. Participants were classified into three chemotherapy response categories: platinum-refractory, platinum-resistant or platinum-sensitive. A significant positive correlation was found between elevated inflammatory status on the day of surgery and longer disease-free interval. SRH measures did not correlate with immune status in participants with OC or a BPM. We identified a correlation between peritoneal microbial features and chemotherapy response. We conclude that immune dysbiosis may be useful in predicting OC recurrence. The immune findings reported here set the framework for additional studies utilizing immune profiles to predict platinum-based chemotherapy responsiveness in OC.