RESUMO
Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.
Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Progressão da Doença , Imunidade Inata , Imunoterapia , Linfócitos/imunologia , Animais , Comunicação Celular/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Neoplasias do Colo/microbiologia , Fezes/microbiologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade Inata/efeitos dos fármacos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Invasividade Neoplásica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Doadores de TecidosRESUMO
Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.
Assuntos
Neoplasias do Colo/patologia , Células Mieloides/metabolismo , Análise de Célula Única/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases/genética , Linfócitos T CD8-Positivos/imunologia , China , Neoplasias do Colo/terapia , Neoplasias Colorretais/patologia , Células Dendríticas/imunologia , Feminino , Humanos , Imunoterapia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Análise de Sequência de RNA/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Proteogenômica/métodos , Apoptose/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos , Proliferação de Células/genética , Neoplasias do Colo/metabolismo , Genômica/métodos , Glicólise , Humanos , Instabilidade de Microssatélites , Mutação , Fosforilação , Estudos Prospectivos , Proteômica/métodos , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismoRESUMO
Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.
Assuntos
Linfócitos T CD8-Positivos/enzimologia , Neoplasias do Colo/enzimologia , Metabolismo Energético , Ativação Linfocitária , Linfócitos do Interstício Tumoral/enzimologia , Melanoma Experimental/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Citotoxicidade Imunológica , Estabilidade Enzimática , Feminino , Glucosefosfato Desidrogenase/metabolismo , Glicólise , Hexoquinase/genética , Hexoquinase/metabolismo , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/transplante , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADP/metabolismo , Fenótipo , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Microambiente Tumoral , Quinase Induzida por NF-kappaBRESUMO
Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias do Colo/metabolismo , Metabolismo Energético , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/metabolismo , Timo/metabolismo , Microambiente Tumoral , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Linhagem da Célula , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Feminino , Glucose/metabolismo , Glicólise , Humanos , Imunoterapia Adotiva , Interferon gama/metabolismo , Interleucina-17/metabolismo , Metabolismo dos Lipídeos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/transplante , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Técnicas de Cultura de Órgãos , Fenótipo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Timo/imunologia , Carga TumoralRESUMO
DNA mismatch repair-deficient (MMR-d) cancers present an abundance of neoantigens that is thought to explain their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. Here, in contrast to other cancer types3-5, we observed that 20 out of 21 (95%) MMR-d cancers with genomic inactivation of ß2-microglobulin (encoded by B2M) retained responsiveness to ICB, suggesting the involvement of immune effector cells other than CD8+ T cells in this context. We next identified a strong association between B2M inactivation and increased infiltration by γδ T cells in MMR-d cancers. These γδ T cells mainly comprised the Vδ1 and Vδ3 subsets, and expressed high levels of PD-1, other activation markers, including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors. In vitro, PD-1+ γδ T cells that were isolated from MMR-d colon cancers exhibited enhanced reactivity to human leukocyte antigen (HLA)-class-I-negative MMR-d colon cancer cell lines and B2M-knockout patient-derived tumour organoids compared with antigen-presentation-proficient cells. By comparing paired tumour samples from patients with MMR-d colon cancer that were obtained before and after dual PD-1 and CTLA-4 blockade, we found that immune checkpoint blockade substantially increased the frequency of γδ T cells in B2M-deficient cancers. Taken together, these data indicate that γδ T cells contribute to the response to immune checkpoint blockade in patients with HLA-class-I-negative MMR-d colon cancers, and underline the potential of γδ T cells in cancer immunotherapy.
Assuntos
Neoplasias do Colo , Genes MHC Classe I , Antígenos de Histocompatibilidade Classe I , Inibidores de Checkpoint Imunológico , Imunoterapia , Receptores de Antígenos de Linfócitos T gama-delta , Linfócitos T , Humanos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética , Reparo de Erro de Pareamento de DNA/genética , Receptores KIR , Linhagem Celular Tumoral , Organoides , Apresentação de Antígeno , Genes MHC Classe I/genéticaRESUMO
Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity.
Assuntos
Antígenos de Diferenciação/metabolismo , Neoplasias do Colo/imunologia , DNA Mitocondrial/imunologia , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Animais , Anticorpos Bloqueadores/uso terapêutico , Antígeno CD47/imunologia , Antígeno CD47/metabolismo , Células Cultivadas , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Apresentação Cruzada , Modelos Animais de Doenças , Humanos , Interferon Tipo I/metabolismo , Macrófagos/imunologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Evasão TumoralRESUMO
Nanoparticle (NP)-based mRNA cancer vaccines hold great promise to realize personalized cancer treatments. To advance this technology requires delivery formulations for efficient intracellular delivery to antigen-presenting cells. We developed a class of bioreducible lipophilic poly(beta-amino ester) nanocarriers with quadpolymer architecture. The platform is agnostic to the mRNA sequence, with one-step self-assembly allowing for delivery of multiple antigen-encoding mRNAs as well as codelivery of nucleic acid-based adjuvants. We examined structure-function relationships for NP-mediated mRNA delivery to dendritic cells (DCs) and identified that a lipid subunit of the polymer structure was critical. Following intravenous administration, the engineered NP design facilitated targeted delivery to the spleen and preferential transfection of DCs without the need for surface functionalization with targeting ligands. Treatment with engineered NPs codelivering antigen-encoding mRNA and toll-like receptor agonist adjuvants led to robust antigen-specific CD8+ T cell responses, resulting in efficient antitumor therapy in in vivo models of murine melanoma and colon adenocarcinoma.
Assuntos
Adenocarcinoma , Vacinas Anticâncer , Neoplasias do Colo , Nanopartículas , Animais , Camundongos , Humanos , Células Dendríticas , Baço , Ligantes , RNA Mensageiro/genética , Adenocarcinoma/patologia , Neoplasias do Colo/terapia , Neoplasias do Colo/patologia , Antígenos , Adjuvantes Imunológicos , Vacinação , Nanopartículas/química , Polímeros/químicaRESUMO
BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).
Assuntos
Antineoplásicos , Quimioterapia Adjuvante , DNA Tumoral Circulante , Neoplasias do Colo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália , Quimioterapia Adjuvante/métodos , DNA Tumoral Circulante/análise , DNA Tumoral Circulante/sangue , Neoplasias do Colo/sangue , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Oxaliplatina/uso terapêuticoRESUMO
Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.
Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia , Animais , Anticorpos Monoclonais/administração & dosagem , Apoptose , Azetidinas/administração & dosagem , Azetidinas/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Sinergismo Farmacológico , Tratamento Farmacológico , Quimioterapia Combinada , MAP Quinases Reguladas por Sinal Extracelular , Humanos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Transplante de Neoplasias , Piperidinas/administração & dosagem , Piperidinas/farmacologiaRESUMO
Photodynamic therapy (PDT) represents an emerging strategy to treat various malignancies, including colorectal cancer (CC), the third most common cancer type. This work presents an engineered M13 phage retargeted towards CC cells through pentavalent display of a disulfide-constrained peptide nonamer. The M13CC nanovector was conjugated with the photosensitizer Rose Bengal (RB), and the photodynamic anticancer effects of the resulting M13CC-RB bioconjugate were investigated on CC cells. We show that upon irradiation M13CC-RB is able to impair CC cell viability, and that this effect depends on i) photosensitizer concentration and ii) targeting efficiency towards CC cell lines, proving the specificity of the vector compared to unmodified M13 phage. We also demonstrate that M13CC-RB enhances generation and intracellular accumulation of reactive oxygen species (ROS) triggering CC cell death. To further investigate the anticancer potential of M13CC-RB, we performed PDT experiments on 3D CC spheroids, proving, for the first time, the ability of engineered M13 phage conjugates to deeply penetrate multicellular spheroids. Moreover, significant photodynamic effects, including spheroid disruption and cytotoxicity, were readily triggered at picomolar concentrations of the phage vector. Taken together, our results promote engineered M13 phages as promising nanovector platform for targeted photosensitization, paving the way to novel adjuvant approaches to fight CC malignancies.
Assuntos
Bacteriófagos , Neoplasias do Colo , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Morte Celular , Rosa Bengala/farmacologia , Rosa Bengala/química , Neoplasias do Colo/terapiaRESUMO
The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) provides unique opportunities for cancer target discovery using protein expression. Proteomics data from CPTAC tumor types have been primarily generated using a multiplex tandem mass tag (TMT) approach, which is designed to provide protein quantification relative to reference samples. However, relative protein expression data are suboptimal for prioritization of targets within a tissue type, which requires additional reprocessing of the original proteomics data to derive absolute quantitation estimation. We evaluated the feasibility of using differential protein analysis coupled with intensity-based absolute quantification (iBAQ) to identify tumor-enriched and highly expressed cell surface antigens, employing tandem mass tag (TMT) proteomics data from CPTAC. Absolute quantification derived from TMT proteomics data was highly correlated with that of label-free proteomics data from the CPTAC colon adenocarcinoma cohort, which contains proteomics data measured by both approaches. We validated the TMT-iBAQ approach by comparing the iBAQ value to the receptor density value of HER2 and TROP2 measured by flow cytometry in about 30 selected breast and lung cancer cell lines from the Cancer Cell Line Encyclopedia. Collections of these tumor-enriched and highly expressed cell surface antigens could serve as a valuable resource for the development of cancer therapeutics, including antibody-drug conjugates and immunotherapeutic agents.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Proteômica , Neoplasias do Colo/terapia , Linhagem CelularRESUMO
Management of colon cancer has changed over the last few decades. We assessed the trends in management and outcomes using the US National Cancer Database (NCDB). A retrospective analysis of all patients with colonic adenocarcinoma between 2005 and 2019 was conducted. The cohort was divided into three equal time periods: Period 1 (2005-2009), Period 2 (2010-2014), and Period 3 (2015-2019) to examine treatment and outcomes trends. The primary outcome was 5-year overall survival (OS). The study included 923,275 patients. A significant increase in patients with stage IV disease was noted in Period 3 compared to Period 1 (47.9% vs. 27.9%, respectively), whereas a reciprocal reduction was seen in patients with locally advanced disease (stage II: 20.8%-12%; stage III: 14.5%-7.7%). Use of immunotherapy significantly increased from 0.3% to 7.6%. Mean 5-year OS increased (43.6 vs. 42.1 months) despite the increase in metastatic disease and longer time from diagnosis to definitive surgery (7 vs. 14 days). A reduction in 30-day readmission (5.1%-4.2%), 30- (3.9%-2.8%), and 90-day mortality (7.1%-5%) was seen. Laparoscopic and robotic surgery increased from 45.8% to 53.1% and 2.9% to 12.7%, respectively. Median postoperative length of hospital stay decreased by 2 days. Rate of positive resection margins (7.2%-6%) and median number of examined lymph nodes (14-16) also improved. Minimally invasive surgery and immunotherapy for colon cancer significantly increased in recent years. Patient outcomes including OS improved over time.
Assuntos
Neoplasias do Colo , Bases de Dados Factuais , Humanos , Neoplasias do Colo/terapia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/epidemiologia , Estados Unidos/epidemiologia , Masculino , Feminino , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Adenocarcinoma/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Estadiamento de Neoplasias , Resultado do Tratamento , Imunoterapia/métodos , Idoso de 80 Anos ou mais , AdultoRESUMO
BACKGROUND: The objective of this study was to quantify disparities in cancer treatment delivery between minority-serving hospitals (MSHs) and non-MSHs for breast, prostate, nonsmall cell lung, and colon cancers from 2010 to 2019 and to estimate the impact of improving care at MSHs on national disparities. METHODS: Data from the National Cancer Database (2010-2019) identified patients who were eligible for definitive treatments for the specified cancers. Hospitals in the top decile by minority patient proportion were classified as MSHs. Multivariable logistic regression adjusted for patient and hospital characteristics compared the odds of receiving definitive treatment at MSHs versus non-MSHs. A simulation was used to estimate the increase in patients receiving definitive treatment if MSH care matched the levels of non-MSH care. RESULTS: Of 2,927,191 patients from 1330 hospitals, 9.3% were treated at MSHs. MSHs had significant lower odds of delivering definitive therapy across all cancer types (adjusted odds ratio: breast cancer, 0.83; prostate cancer, 0.69; nonsmall cell lung cancer, 0.73; colon cancer, 0.81). No site of care-race interaction was significant for any of the cancers (p > .05). Equalizing treatment rates at MSHs could result in 5719 additional patients receiving definitive treatment over 10 years. CONCLUSIONS: The current findings underscore systemic disparities in definitive cancer treatment delivery between MSHs and non-MSHs for breast, prostate, nonsmall cell lung, and colon cancers. Although targeted improvements at MSHs represent a critical step toward equity, this study highlights the need for integrated, system-wide efforts to address the multifaceted nature of racial and ethnic health disparities. Enhancing care at MSHs could serve as a pivotal strategy in a broader initiative to achieve health care equity for all.
Assuntos
Neoplasias da Mama , Neoplasias do Colo , Disparidades em Assistência à Saúde , Hospitais , Neoplasias Pulmonares , Neoplasias da Próstata , Humanos , Masculino , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Feminino , Neoplasias da Próstata/terapia , Neoplasias da Próstata/etnologia , Neoplasias do Colo/terapia , Neoplasias do Colo/etnologia , Neoplasias da Mama/terapia , Neoplasias da Mama/etnologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/etnologia , Hospitais/estatística & dados numéricos , Pessoa de Meia-Idade , Idoso , Estados Unidos , Grupos Minoritários/estatística & dados numéricosRESUMO
OBJECTIVES: This study investigated the potential of combining PTT with dendritic cell (DC)-based immunotherapy and anti-PD-L1 immune checkpoint blockade (ICB) therapy against colorectal cancer and elucidated the underlying mechanisms. METHODS: The CT26 tumour-bearing mice were divided into seven treatment groups: control, atezolizumab (A), dendritic cells (DC), pAuNSs-mediated PTT (PTT), PTT combined with atezolizumab (PTT + A), PTT combined with dendritic cells (PTT + DC), and PTT combined with dendritic cells and atezolizumab (PTT + DC + A). Therapeutic efficacy was monitored. RESULTS: PTT upregulated most immune cell membrane receptor genes, including PD-L1, and downregulated genes associated with antigen presentation and T cell activation. Although the PTT + A and PTT + DC treatments showed partial tumour growth retardation, the combination of PTT with DCs and atezolizumab (PTT + DC + A) exhibited the most significant antitumour effect, with a complete remission rate of 50% and prolonged survival. On day 14, tumour samples from non-responsive mice revealed insufficient recruitment of T cells as the reason for uncured tumours. Notably, mice cured with PTT + DC and PTT + DC + A treatments showed no detectable lung nodules. CONCLUSION: This study demonstrated that the combination of PTT with DC-based immunotherapy and atezolizumab effectively overcomes the non-sensitive nature of CT26 tumours. These findings highlight the potential of this combination approach for colorectal cancer treatment.
Assuntos
Carcinoma , Neoplasias do Colo , Camundongos , Animais , Terapia Fototérmica , Neoplasias do Colo/terapia , Imunoterapia , Ouro , Linhagem Celular TumoralRESUMO
BACKGROUND: Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients. METHODS: We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues. RESULTS: We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy. CONCLUSIONS: The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy.
Assuntos
Neoplasias do Colo , Neutrófilos , Humanos , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Fatores de Risco , Algoritmos , ImunoterapiaRESUMO
BACKGROUND: The global prevalence and metastasis rates of colon adenocarcinoma (COAD) are high, and therapeutic success is limited. Although previous research has primarily explored changes in gene phenotypes, the incidence rate of COAD remains unchanged. Metabolic reprogramming is a crucial aspect of cancer research and therapy. The present study aims to develop cluster and polygenic risk prediction models for COAD based on glucose metabolism pathways to assess the survival status of patients and potentially identify novel immunotherapy strategies and related therapeutic targets. METHODS: COAD-specific data (including clinicopathological information and gene expression profiles) were sourced from The Cancer Genome Atlas (TCGA) and two Gene Expression Omnibus (GEO) datasets (GSE33113 and GSE39582). Gene sets related to glucose metabolism were obtained from the MSigDB database. The Gene Set Variation Analysis (GSVA) method was utilized to calculate pathway scores for glucose metabolism. The hclust function in R, part of the Pheatmap package, was used to establish a clustering system. The mutation characteristics of identified clusters were assessed via MOVICS software, and differentially expressed genes (DEGs) were filtered using limma software. Signature analysis was performed using the least absolute shrinkage and selection operator (LASSO) method. Survival curves, survival receiver operating characteristic (ROC) curves and multivariate Cox regression were analyzed to assess the efficacy and accuracy of the signature for prognostic prediction. The pRRophetic program was employed to predict drug sensitivity, with data sourced from the Genomics of Drug Sensitivity in Cancer (GDSC) database. RESULTS: Four COAD subgroups (i.e., C1, C2, C3 and C4) were identified based on glucose metabolism, with the C4 group having higher survival rates. These four clusters were bifurcated into a new Clust2 system (C1 + C2 + C3 and C4). In total, 2175 DEGs were obtained (C1 + C2 + C3 vs. C4), from which 139 prognosis-related genes were identified. ROC curves predicting 1-, 3- and 5-year survival based on a signature containing nine genes showed an area under the curve greater than 0.7. Meanwhile, the study also found this feature to be an important predictor of prognosis in COAD and accordingly assessed the risk score, with higher risk scores being associated with a worse prognosis. The high-risk and low-risk groups responded differently to immunotherapy and chemotherapeutic agents, and there were differences in functional enrichment pathways. CONCLUSIONS: This unique signature based on glucose metabolism may potentially provide a basis for predicting patient prognosis, biological characteristics and more effective immunotherapy strategies for COAD.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/terapia , Imunoterapia , Metabolismo dos Carboidratos , GlucoseRESUMO
BACKGROUND: Disparities in colon cancer care and outcomes by race/ethnicity, socioeconomic status (SES), and insurance are well recognized; however, the extent to which inequalities are driven by patient factors versus variation in hospital performance remains unclear. We sought to compare disparities in care delivery and outcomes at low- and high-performing hospitals. METHODS: We identified patients with stage I-III colon adenocarcinoma from the 2012-2017 National Cancer Database. Adequate lymphadenectomy and timely adjuvant chemotherapy administration defined hospital performance. Multilevel regression models evaluated disparities by race/ethnicity, SES, and insurance at the lowest- and highest-performance quartile hospitals. RESULTS: Of 92,573 patients from 704 hospitals, 45,982 (49.7%) were treated at 404 low-performing hospitals and 46,591 (50.3%) were treated at 300 high-performing hospitals. Low-performing hospitals treated more non-Hispanic (NH) Black, Hispanic, low SES, and Medicaid patients (all p < 0.01). Among low-performing hospitals, patients with low versus high SES (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82-0.92), and Medicare (OR 0.90, 95% CI 0.85-0.96) and Medicaid (OR 0.88, 95% CI 0.80-0.96) versus private insurance, had decreased odds of receiving high-quality care. At high-performing hospitals, NH Black versus NH White patients (OR 0.83, 95% CI 0.72-0.95) had decreased odds of receiving high-quality care. Low SES, Medicare, Medicaid, and uninsured patients had worse overall survival at low- and high-performing hospitals (all p < 0.01). CONCLUSION: Disparities in receipt of high-quality colon cancer care occurred by SES and insurance at low-performing hospitals, and by race at high-performing hospitals. However, survival disparities by SES and insurance exist irrespective of hospital performance. Future steps include improving low-performing hospitals and identifying mechanisms affecting survival disparities.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Humanos , Idoso , Estados Unidos/epidemiologia , Medicare , Disparidades Socioeconômicas em Saúde , Adenocarcinoma/terapia , Neoplasias do Colo/terapia , Resultado do Tratamento , Fatores Socioeconômicos , Disparidades em Assistência à SaúdeRESUMO
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.
Assuntos
Neoplasias do Colo , Eosinófilos , Imunidade Inata , Camundongos Knockout , Células T Invariantes Associadas à Mucosa , Animais , Células T Invariantes Associadas à Mucosa/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Camundongos , Humanos , Imunidade Inata/imunologia , Eosinófilos/imunologia , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Linhagem Celular Tumoral , Técnicas de Cocultura , Proteínas de HomeodomínioRESUMO
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.