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Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer progression. Moreover, leukocyte trafficking depended on the integrins CD11a/CD49d, and CD11a/CD49d blockade led to significant tumor burden reduction in mice. Importantly, preventing circulating Treg recruitment through depletion or sequestration in lymph nodes was sufficient to decrease tumor burden, indicating that Treg migration was crucial for suppressing antitumor immunity. These findings underscore the dynamic nature of the immune compartment within mouse lung tumors and demonstrate the relevance of a temporal map of leukocyte recruitment into tumors, thereby advancing our understanding of leukocyte migration in the context of tumor development.
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PURPOSE: The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection. EXPERIMENTAL DESIGN: TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC. Prospective longitudinal plasma collection for ctDNA occurred pre- and postsurgery, post-ACT, every 3 months for year 1 and every 6 months in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2-year recurrence-free survival (RFS) by postoperative ctDNA detection (NCT04050345). RESULTS: Between December 2016 and August 2022, 1,203 were patients enrolled. Plasma samples (n = 997) from 214 patients were analyzed. One hundred forty-three patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; two (1.4%) stage I, 64 (44.8%) stage II, and 77 (53.8%) stage III. Median follow-up was 30.3 months (95% CI, 29.5-31.3). Two-year RFS was 91.1% in patients with ctDNA not detected postoperatively and 50.4% in those with ctDNA detected [HR, 6.5 (2.96-14.5); P < 0.0001]. Landmark negative predictive value (NPV) was 91.2% (95% CI, 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI, 42.2-79.3) and 85.9% (95% CI, 78.9-91.3), respectively. The median lead time from ctDNA detection to radiological recurrence was 7.3 months (IQR, 3.3-12.5; n = 9). CONCLUSIONS: Tissue-free MRD detection with longitudinal sampling predicts recurrence in patients with stage I to III CRC without the need for tissue sequencing. The UK TRACC Part C study is currently investigating the potential for ACT de-escalation in patients with undetectable postoperative ctDNA, given the high NPV indicating a low likelihood of residual disease.
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Biomarcadores de Tumor , ADN Tumoral Circulante , Neoplasias Colorrectales , Metilación de ADN , Neoplasia Residual , Humanos , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/cirugía , Masculino , Femenino , Biopsia Líquida/métodos , Anciano , Persona de Mediana Edad , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Biomarcadores de Tumor/genética , Estudios Prospectivos , Adulto , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/diagnóstico , Estadificación de Neoplasias , Reino Unido , Anciano de 80 o más Años , Genómica/métodos , Mutación , PronósticoRESUMEN
Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/ß-catenin, mitogen-activated protein kinase, and TGF-ß receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Antígeno B7-H1 , Filogenia , Neoplasias Colorrectales/patología , Microambiente Tumoral/genéticaRESUMEN
Background: As liver metastasis is the most common cause of mortality in patients with colorectal cancer, studying colorectal cancer liver metastasis (CLM) microenvironment is essential for improved understanding of tumor biology and to identify novel therapeutic targets. Methods: We used multiplex immunofluorescence platform to study tumor associated macrophage (TAM) polarization and adaptive T cell subtypes in tumor samples from 105 CLM patients (49 without and 56 with preoperative chemotherapy). Results: CLM exhibited M2 macrophage polarization, and helper T cells were the prevalent adaptive T cell subtype. The density of total, M2 and TGFß-expressing macrophages, and regulatory T cells was lower in CLM treated with preoperative chemotherapy. CLM with right-sided primary demonstrated enrichment of TGFß-expressing macrophages, and with left-sided primary had higher densities of helper and cytotoxic T cells. In multivariate analysis, high density of M2 macrophages correlated with longer recurrence-free survival (RFS) in the entire cohort [hazard ratio (HR) 0.425, 95% CI 0.219-0.825, p=0.011) and in patients without preoperative chemotherapy (HR 0.45, 95% CI 0.221-0.932, p=0.032). High pSMAD3-expressing macrophages were associated with shorter RFS in CLM after preoperative chemotherapy. Conclusions: Our results highlight the significance of a multi-marker approach to define the macrophage subtypes and identify M2 macrophages as a predictor of favorable prognosis in CLM.
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Immunotherapy has only had a modest impact on the treatment of advanced GI malignancies. Microsatellite-stable colorectal cancer and pancreatic adenocarcinoma, the most common GI tumors, have not benefited from treatment with standard immune checkpoint inhibitors. With this huge unmet need, multiple approaches are being tried to overcome barriers to better anticancer outcomes. This article reviews a number of novel approaches to immunotherapy for these tumors. These include the use of novel checkpoint inhibitors such as a modified anti-cytotoxic T lymphocyte-associated antigen-4 antibody and antibodies to lymphocyte-activation gene 3, T cell immunoreceptor with immunoglobulin and ITIM domains, T-cell immunoglobulin-3, CD47, and combinations with signal transduction inhibitors. We will discuss other trials that aim to elicit an antitumor T-cell response using cancer vaccines and oncolytic viruses. Finally, we review attempts to replicate in GI cancers the frequent and durable responses seen in hematologic malignancies with immune cell therapies.
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Adenocarcinoma , Antineoplásicos , Neoplasias Gastrointestinales , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Gastrointestinales/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Linfocitos T , InmunoterapiaRESUMEN
Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.
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Inmunoterapia , Neoplasias , Humanos , Antígeno B7-H1 , Neoplasias/tratamiento farmacológico , Ensayos Clínicos como Asunto , Inhibidores de Puntos de Control Inmunológico/administración & dosificaciónRESUMEN
BACKGROUND: Circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) is emerging as a biomarker to predict recurrence in patients with curatively treated early stage colorectal cancer (CRC). ctDNA risk stratifies patients to guide adjuvant treatment decisions. We are conducting the UK's first multi-centre, prospective, randomised study to determine whether a de-escalation strategy using ctDNA to guide adjuvant chemotherapy (ACT) decisions is non-inferior to standard of care (SOC) chemotherapy, as measured by 3-year disease free survival (DFS) in patients with resected CRC with no evidence of MRD (ctDNA negative post-operatively). In doing so we may be able to spare patients unnecessary chemotherapy and associated toxicity and achieve significant cost savings for the National Health Service (NHS). METHODS: We are recruiting patients with fully resected high risk stage II and stage III CRC who are being considered for ACT into the study which uses results from a plasma-only ctDNA assay to guide treatment decisions. Eligible patients are randomised 1:1 to receive ctDNA-guided chemotherapy versus SOC chemotherapy. The primary endpoint is the difference in DFS at 3 years between the trial arms. Secondary endpoints include the proportion of patients in the ctDNA-guided arm who are ctDNA negative post-operatively and receive de-escalated ACT compared to the standard arm, the difference in overall survival (OS), neurotoxicity and quality of life between the arms, and the cost-effectiveness of ctDNA-guided therapy compared to SOC treatment. We hypothesise that using a ctDNA-guided approach to ACT decisions is non-inferior to SOC. Target accrual is 1621 patients over 4 years, which will provide a power of 80% with an alpha of 0.1 to demonstrate non-inferiority with a margin of 1.25 in survival of the ctDNA-guided approach compared to SOC. We anticipate approximately 50 UK centres will participate. The study opened with the Guardant Reveal plasma-only ctDNA assay in August 2022. DISCUSSION: The trial will determine whether ctDNA guided ACT is non-inferior to SOC ACT in patients with fully resected high risk stage II and stage III resected CRC, with the potential to significantly reduce unnecessary ACT and the toxicity associated with it. TRIAL REGISTRATION: NCT04050345.
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Neoplasias Colorrectales , Medicina Estatal , Humanos , Calidad de Vida , Estudios Prospectivos , Nivel de Atención , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Quimioterapia Adyuvante/métodos , Supervivencia sin EnfermedadRESUMEN
In a recent issue of Cancer Cell, Amodio and colleagues report an interesting method of modulating immunosurveillance in colorectal tumors with DNA mismatch repair (MMR) heterogeneity.1 By pharmacologically enriching the MMR deficient (MMRd) component using 6-thioguanine, they demonstrate improved tumor control in murine models.
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Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Animales , Ratones , Reparación de la Incompatibilidad de ADN/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Tioguanina/uso terapéuticoRESUMEN
[Figure: see text].
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Inhibidores de la Angiogénesis/efectos adversos , Endotelio Vascular/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hipertensión/inducido químicamente , Indazoles/efectos adversos , Pirimidinas/efectos adversos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sulfonamidas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Gasto Cardíaco/efectos de los fármacos , Endotelio Vascular/fisiopatología , Femenino , Humanos , Hipertensión/fisiopatología , Indazoles/administración & dosificación , Indazoles/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Rigidez Vascular/efectos de los fármacosRESUMEN
PURPOSE: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs. EXPERIMENTAL DESIGN: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. RESULTS: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer). CONCLUSIONS: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Expresión Génica , MicroARNs/genética , Anciano , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/mortalidad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Pronóstico , Retratamiento , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213 This article is highlighted in the In This Issue feature, p. 1195.
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Neoplasias Colorrectales/diagnóstico , Biopsia Líquida/métodos , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Evolución Clonal , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Tiempo de Tratamiento , Insuficiencia del TratamientoRESUMEN
With further understanding of the biology of gastric and gastroesophageal adenocarcinomas, strides are being made to find effective treatments through novel trial designs. This article focuses on the ongoing trials of drugs targeting specific hallmarks of gastric and gastroesophageal cancers, including oncogene addiction proliferative pathways (fibroblast growth factor receptor 2 amplified tumors), stem cell inhibition, apoptotic induction through claudin inhibitors, and matrix metalloproteinase inhibition. In developing novel therapeutics in treatment of patients with gastroesophageal adenocarcinomas, parallel research efforts to refine target population and biomarkers are crucial, and targeting the tumor genomics and microenvironment may be key in improving overall survival.
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Adenocarcinoma , Antineoplásicos/uso terapéutico , Neoplasias Esofágicas , Proteínas de Neoplasias , Neoplasias Gástricas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Claudinas/antagonistas & inhibidores , Claudinas/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Gelatinasas/antagonistas & inhibidores , Gelatinasas/genética , Gelatinasas/metabolismo , Amplificación de Genes , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
This study introduces the use of 'error-category mapping' in the interpretation of pharmacokinetic (PK) model parameter results derived from dynamic contrast-enhanced (DCE-) MRI data. Eleven patients with metastatic renal cell carcinoma were enrolled in a multiparametric study of the treatment effects of bevacizumab. For the purposes of the present analysis, DCE-MRI data from two identical pre-treatment examinations were analysed by application of the extended Tofts model (eTM), using in turn a model arterial input function (AIF), an individually-measured AIF and a sample-average AIF. PK model parameter maps were calculated. Errors in the signal-to-gadolinium concentration ([Gd]) conversion process and the model-fitting process itself were assigned to category codes on a voxel-by-voxel basis, thereby forming a colour-coded 'error-category map' for each imaged slice. These maps were found to be repeatable between patient visits and showed that the eTM converged adequately in the majority of voxels in all the tumours studied. However, the maps also clearly indicated sub-regions of low Gd uptake and of non-convergence of the model in nearly all tumours. The non-physical condition ve ≥ 1 was the most frequently indicated error category and appeared sensitive to the form of AIF used. This simple method for visualisation of errors in DCE-MRI could be used as a routine quality-control technique and also has the potential to reveal otherwise hidden patterns of failure in PK model applications.
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Carcinoma de Células Renales/patología , Medios de Contraste/química , Medios de Contraste/farmacocinética , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias Renales/patología , Imagen por Resonancia Magnética , Algoritmos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Área Bajo la Curva , Bevacizumab , Carcinoma de Células Renales/diagnóstico , Humanos , Neoplasias Renales/diagnóstico , Modelos Teóricos , Metástasis de la Neoplasia , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
PURPOSE OF REVIEW: The targeting of receptor tyrosine kinases (RTKs) has been a major area for breast cancer therapy, exemplified by the targeting of HER2-amplified breast cancer. RECENT FINDINGS: We review the data on the activation of RTKs in HER2-negative breast cancer, and discuss the clinical translational challenge of identifying cancers that are reliant on a specific kinase for growth and survival. Substantial evidence suggests that subsets of breast cancer may be reliant on specific kinases, and that this could be exploited therapeutically. The heterogeneity of breast cancer, however, and the potential for adaptive switching between RTKs after inhibition of a single RTK, present challenges to targeting individual RTKs in the clinic SUMMARY: Targeting of RTKs in HER2-negative breast cancer presents a major therapeutic opportunity in breast cancer, although robust selection strategies will be required to identify cancers with activation of specific RTKs if this potential is to be realized.