Recent Submissions

  • Comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom

    Robbins H A; Alcala K; Swerdlow A J; Schoemaker M J; Wareham N; Travis R C; Crosbie Philip A J; Callister M; Baldwin D R; Landy R; et al. (2021)
    Background: The National Health Service England (NHS) classifies individuals as eligible for lung cancer screening using two risk prediction models, PLCOm2012 and Liverpool Lung Project-v2 (LLPv2). However, no study has compared the performance of lung cancer risk models in the UK. Methods: We analysed current and former smokers aged 40-80 years in the UK Biobank (N = 217,199), EPIC-UK (N = 30,813), and Generations Study (N = 25,777). We quantified model calibration (ratio of expected to observed cases, E/O) and discrimination (AUC). Results: Risk discrimination in UK Biobank was best for the Lung Cancer Death Risk Assessment Tool (LCDRAT, AUC = 0.82, 95% CI = 0.81-0.84), followed by the LCRAT (AUC = 0.81, 95% CI = 0.79-0.82) and the Bach model (AUC = 0.80, 95% CI = 0.79-0.81). Results were similar in EPIC-UK and the Generations Study. All models overestimated risk in all cohorts, with E/O in UK Biobank ranging from 1.20 for LLPv3 (95% CI = 1.14-1.27) to 2.16 for LLPv2 (95% CI = 2.05-2.28). Overestimation increased with area-level socioeconomic status. In the combined cohorts, USPSTF 2013 criteria classified 50.7% of future cases as screening eligible. The LCDRAT and LCRAT identified 60.9%, followed by PLCOm2012 (58.3%), Bach (58.0%), LLPv3 (56.6%), and LLPv2 (53.7%). Conclusion: In UK cohorts, the ability of risk prediction models to classify future lung cancer cases as eligible for screening was best for LCDRAT/LCRAT, very good for PLCOm2012, and lowest for LLPv2. Our results highlight the importance of validating prediction tools in specific countries.
  • Technology clinical trials: Turning innovation into patient benefit

    Royle, J. K.; Hughes, Andrew M; Stephenson, L; Landers, D.; digital Experimental Cancer Medicine Team, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. (2021)
    Health care needs to continuously evolve and innovate to maintain the health of populations. Technology has the potential to enable better patient engagement and ownership, as well as optimise therapeutic interventions and data-science approaches to facilitate improved health care decisions. Yet, to date, technological innovation has not resulted in the rate of change that could have been predicted from other sectors. This article discusses multiple reasons for this and proposes a newly tested and deployed solution: the technology clinical trial. The technology clinical trial methodology has been developed through working directly with patients, clinical and medical devicetrial experts. This approach enables researchers to use the complex environment of health care as an opportunity to transform the pace of innovation and create new care pathways. Instead of testing a single innovation, researchers can 'step back' and systematically review all areas of the patient's journey for potential optimization. Then integrate novel data science, technological advances, process updates, behavioural science, and patient engagement to co-create a streamlined multidisciplinary solution. As a result, this research has the potential for larger advances due to the emergent benefits that can arise when the individual elements work together as a whole. These potential benefits are then robustly tested, characterised and measured in the trial environment to ensure that future application of the innovative pathway is supported by the robust empirical data health care requires.
  • Fibroblast growth factor receptors (FGFRs) and noncanonical partners in cancer signaling

    Ferguson, H. R.; Smith, M. P; Francavilla, Chiara; Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, Manchester M13 9PT, (2021)
    Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.
  • Correction: Comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom

    Robbins, H. A.; Alcala, K.; Swerdlow, A. J.; Schoemaker, M. J.; Wareham, N.; Travis, R. C.; Crosbie, Philip A J; Callister, M.; Baldwin, D. R.; Landy, R; et al. (2021)
  • Salvage stereotactic body radiotherapy (SBRT) for intraprostatic relapse after prostate cancer radiotherapy: An ESTRO ACROP Delphi consensus

    Jereczek-Fossa, B. A.; Marvaso, G.; Zaffaroni, M.; Gugliandolo, S. G.; Zerini, D.; Corso, F.; Gandini, S.; Alongi, F.; Bossi, A.; Cornford, P.; et al. (2021)
    Background and purpose: Between 30% and 47% of patients treated with definitive radiotherapy (RT) for prostate cancer are at risk of intraprostatic recurrence during follow-up. Re-irradiation with stereotactic body RT (SBRT) is emerging as a feasible and safe therapeutic option. However, no consensus or guidelines exist on this topic. The purpose of this ESTRO ACROP project is to investigate expert opinion on salvage SBRT for intraprostatic relapse after RT. Materials and methods: A 40-item questionnaire on salvage SBRT was prepared by an internal committee and reviewed by a panel of leading radiation oncologists plus a urologist expert in prostate cancer. Following the procedure of a Delphi consensus, 3 rounds of questionnaires were sent to selected experts on prostate re-irradiation. Results: Among the 33 contacted experts, 18 (54.5%) agreed to participate. At the end of the final round, participants were able to find consensus on 14 out of 40 questions (35% overall) and major agreement on 13 questions (32.5% overall). Specifically, the consensus was reached regarding some selection criteria (no age limit, ECOG 0-1, satisfactory urinary flow), diagnostic procedures (exclusion of metastatic disease, SBRT target defined on the MRI) and therapeutic approach (no need for concomitant ADT, consideration of the first RT dose, validity of Phoenix criteria for salvage SBRT failure). Conclusion: While awaiting the results of ongoing studies, our ESTRO ACROP Delphi consensus may serve as a practical guidance for salvage SBRT. Future research should address the existing disagreements on this promising approach.
  • Correction to: A prototypical non-malignant epithelial model to study genome dynamics and concurrently monitor micro-RNAs and proteins in situ during oncogene-induced senescence

    Komseli, E. S.; Pateras, I. S.; Krejsgaard, T.; Stawiski, K.; Rizou, S. V.; Polyzos, A.; Roumelioti, F. M.; Chiourea, M.; Mourkioti, I.; Paparouna, E.; et al. (2021)
  • Biological effect of silver-modified nanostructured titanium dioxide in cancer

    Lagopati, N.; Kotsinas, A.; Veroutis, D.; Evangelou, K.; Papaspyropoulos, A.; Arfanis, M.; Falaras, P.; Kitsiou, P. V.; Pateras, I.; Bergonzini, A.; et al. (2021)
    Background/aim: Nanomedicine is a promising scientific field that exploits the unique properties of innovative nanomaterials, providing alternative solutions in diagnostics, prevention and therapeutics. Titanium dioxide nanoparticles (TiO2 NPs) have a great spectrum of photocatalytic antibacterial and anticancer applications. The chemical modification of TiO2 optimizes its bioactive performance. The aim of this study was the development of silver modified NPs (Ag/TiO2 NPs) with anticancer potential. Materials and methods: Ag/TiO2 NPs were prepared through the sol-gel method, were fully characterized and were tested on cultured breast cancer epithelial cells (MCF-7 and MDA-MB-231). The MTT colorimetric assay was used to estimate cellular viability. Western blot analysis of protein expression along with a DNA-laddering assay were employed for apoptosis detection. Results and conclusion: We show that photo-activated Ag/TiO2 NPs exhibited significant cytotoxicity on the highly malignant MDA-MB-231 cancer cells, inducing apoptosis, while MCF-7 cells that are characterized by low invasive properties were unaffected under the same conditions.
  • British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021

    Nasr, I.; McGrath, E. J.; Harwood, C. A.; Botting, J.; Buckley, P.; Budny, P. G.; Fairbrother, P.; Fife, K.; Gupta, G.; Hashme, M.; et al. (2021)
    The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of basal cell carcinoma (BCC). The document aims to: offer an appraisal of all relevant literature up to 24th January 2020 focusing on any key developments address important, practical clinical questions relating to the primary guideline objective provide guideline recommendations and if appropriate research recommendations.
  • Influence of the microenvironment on modulation of the host response by typhoid toxin

    Martin, O. C. B.; Bergonzini, A.; Chiloeches, M. L.; Paparouna, E.; Butter, D.; Theodorou, S. D. P.; Haykal, M. M.; Boutet-Robinet, E.; Tebaldi, T.; Wakeham, A.; et al. (2021)
    Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.
  • Risk factors for complications and implant loss after prepectoral implant-based immediate breast reconstruction: medium-term outcomes in a prospective cohort

    Dave, R. V.; Vucicevic, A.; Barrett, E.; Highton, L.; Johnson, R.; Kirwan, Cliona C; Harvey, J. R; Murphy, J.; Nightingale Breast Centre, Manchester University Hospitals NHS Foundation Trust, Wythenshawe Hospital, Manchester (2021)
    Background: Prepectoral implant-based breast reconstruction with acellular dermal matrix has become an increasingly popular option for selected patients. There are no randomized data to demonstrate short- or long-term outcomes. Cohort studies to date have demonstrated safety, but risk factors for complications are unknown. Methods: A prospective cohort study of all patients undergoing prepectoral implant-based breast reconstruction between 2013 and 2019. Clinical factors and those related to reconstruction were analysed in relation to complications and implant loss using univariable and multivariable logistic regression. Results: A total of 469 reconstructions were undertaken in 289 women; the majority of reconstructions were performed using a one-stage direct-to-implant technique with acellular dermal matrix. Median follow-up was 21 (range 2-71) months. Minor complications were seen after 11·2 per cent of reconstructions, major complications after 5·9 per cent, and the rate of implant loss by 3 months was 3·1 per cent. In the final multivariable model, sentinel node biopsy (odds ratio (OR) 5·06, 95 per cent c.i. 2·00 to 12·80), axillary clearance (OR 6·67, 1·17 to 37·94) and adjuvant radiotherapy (OR 7·11, 1·60 to 31·61) were independent risk factors for development of a major complication, and sentinel node biopsy (OR 4·32, 1·23 to 15·22) for implant loss. Conclusion: Prepectoral implant-based breast reconstruction has acceptable medium-term results but careful patient selection is advised.
  • Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy

    Pelly, Victoria S; Moeini, Agrin; Roelofsen, L. M.; Bonavita, Eduardo; Bell, Charlotte R; Hutton, Colin; Blanco-Gomez, Adrian; Banyard, Antonia; Bromley, Christian P; Flanagan, Eimar; et al. (2021)
    Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from non-responders shortly following treatment and identified acute IFN-γ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot.
  • Keratinocyte cancer mortality in kidney transplant recipients

    Shao, E. X.; Betz-Stablein, B.; Khosrotehrani, K.; Campbell, S.; Isbel, N; Green, Adèle C; QIMR Berghofer Medical Research Institute, Herston, Australia. Faculty of Medicine, The University of Queensland, St Lucia, Australia (2021)
    Background: Kidney transplant recipients are at increased risk of developing and dying from keratinocyte cancer. Risk factors for keratinocyte cancer death have not been previously described. Methods: In a cohort of kidney transplant recipients transplanted in Queensland 1995-2014, we identified keratinocyte cancer deaths by searching national transplant and state death registries to March 2020. Standardized keratinocyte cancer mortality rates and mortality ratios were calculated. We used a competing risks model to identify factors associated with keratinocyte cancer death and calculated relative risks (RRs) and 95% confidence intervals (CIs). Results: There were 562 deaths in 1866 kidney transplant recipients (62% males; 86% Caucasian) with 25 934 person-years of follow-up, of which 36 were due to squamous cell carcinoma (SCC) and 1 to basal cell carcinoma (BCC) with standardized mortality rates of 78 (95% CI 53-111) and 2 (95% CI 0.1-11) per 100,000 person-years respectively. The standardized mortality ratio for keratinocyte cancer was 23 (95% CI 23-24). Besides Caucasian ethnicity (associated with 100% of keratinocyte cancer deaths), male sex (RR 3.24 95% CI 1.26-8.33), and older age at transplantation (> 50 versus <50 years RR 3.09 95% CI 1.38-6.89) were associated with increased risk of keratinocyte cancer death. Conclusions: Keratinocyte cancer mortality in kidney transplant recipients is over 20 times higher than in the general population. Most keratinocyte cancer deaths are due to cutaneous SCC, however, BCC can be fatal. Education in skin cancer prevention is essential to avoid unnecessary deaths from keratinocyte cancer amongst kidney transplant recipients.
  • AMPKα loss promotes KRAS-mediated lung tumorigenesis

    La Montagna, Manuela; Shi, Lei; Magee, Peter; Sahoo, Sudhakar; Fassan, M; Garofalo, Michela; Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (2021)
    AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRASG12D increased lung tumour burden and reduced survival in KrasLSLG12D/+/AMPKαfl/fl mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.
  • Response to 'A call to standardize the BCC: SCC ratio': reply from authors

    Jiyad, Z.; Marquart, L; Green, Adèle C; Department of Dermatology, St George's Hospital, London, UK. (2021)
    We thank Ma et al. for suggesting the inclusion of in-situ squamous cell carcinoma (SCC-IS) to the commonly used ratio, basal cell carcinoma (BCC):SCC. Indeed, we concur with the authors that superficial BCC is usually managed similarly to SCC-IS. However, equating superficial BCC with a precursor lesion (SCC-IS) on the basis of similar management approaches, would be a confusing strategy. The strength of the BCC:SCC ratio lies in its ability to facilitate easy comparison of incidence rates between what is generally considered a relatively innocuous keratinocyte tumour (BCC),1 with that of one that carries significant metastatic potential (invasive SCC).2.
  • Early dissemination of circulating tumor cells: biological and clinical insights

    Chemi, Francesca; Mohan, Sumitra; Guevara, Tatiana; Clipson, Alexandra; Rothwell, Dominic G; Dive, Caroline; Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Macclesfield, United Kingdom. (2021)
    Circulating tumor cells (CTCs) play a causal role in the development of metastasis, the major cause of cancer-associated mortality worldwide. In the past decade, the development of powerful cellular and molecular technologies has led to a better understanding of the molecular characteristics and timing of dissemination of CTCs during cancer progression. For instance, genotypic and phenotypic characterization of CTCs, at the single cell level, has shown that CTCs are heterogenous, disseminate early and could represent only a minor subpopulation of the primary tumor responsible for disease relapse. While the impact of molecular profiling of CTCs has not yet been translated to the clinic, CTC enumeration has been widely used as a prognostic biomarker to monitor treatment response and to predict disease relapse. However, previous studies have revealed a major challenge: the low abundance of CTCs in the bloodstream of patients with cancer, especially in early stage disease where the identification and characterization of subsequently "lethal" cells has potentially the greatest clinical relevance. The CTC field is rapidly evolving with development of new technologies to improve the sensitivity of CTC detection, enumeration, isolation, and molecular profiling. Here we examine the technical and analytical validity of CTC technologies, we summarize current data on the biology of CTCs that disseminate early and review CTC-based clinical applications.
  • Increased melanoma recurrence in patients with multiple primary invasive melanomas

    Green, Adèle C; Hughes, M. C. B.; Williams, G. M.; Malt, M.; Beesley, V. L.; Khosrotehrani, K; Smithers, B. M.; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; CRUK Manchester Institute and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK (2021)
  • High variability in anatomic patterns of cutaneous photodamage: a population-based study

    Betz-Stablein, B.; Llewellyn, S.; Bearzi, P.; Grochulska, K.; Rutjes, C.; Aitken, J. F.; Janda, M.; O'Rouke, P.; Soyer, H. P; Green, Adèle C; et al. (2021)
    Background: Skin cancer is strongly associated with photodamaged skin, but body sites are often referred to as 'exposed' or 'unexposed' to sun without recognizing extent of site-specific variation. Objectives: To assess whole-body patterns of photodamage in an Australian population. Methods: A random sample of adult residents of Queensland underwent imaging across 10 body sites. Photodamage was graded from images using an ordinal photonumeric scale. We used cluster analysis to identify whole-body photodamage patterns and prevalence proportion ratios (PPRs) to assess associated factors. Results: Of 190 adults (median age 52; 58% males), 58% showed severe or moderate-to-severe photodamage on most body sites. A higher proportion of woman had severe photodamage on the arms (upper: P = 0.002, lower: P = 0.034). A higher proportion of men had moderate or severe photodamage on the lower back (P = 0.004). We identified four photodamage patterns: 'severe general' (n = 24, 13%), 'moderate-severe general' (n = 86, 45%), 'moderate-severe v-neck' (n = 40, 21%) and 'mild-moderate upper body' (n = 12, 6%). All participants with 'severe-general' photodamage were >50 years and more likely to have past skin cancer (PPR: 2.54, 95% CI: 1.44-4.49) than those with 'moderate-severe v-neck' photodamage. Those with 'moderate-severe general' photodamage showed similar associations and were more likely female (PPR: 1.33, 95% CI: 1.04-1.69). Past or current smoking was associated with having higher levels of photodamage, with no smokers in those with 'mild-moderate upper body' photodamage. Conclusions: Moderate-to-severe photodamage across much of the body is common in Queensland adults and associated with age, sex, past skin cancer and smoking. Assuming a universal pattern of site-specific sun exposure could lead to spurious correlations, while accurate and objective assessment of site-specific photodamage can add to understanding of the development of sun-associated skin cancers, in particular site-specific skin carcinogenesis. Additionally, degree of site-specific photodamage has the potential to assist skin cancer screening.
  • QUAREP-LiMi: a community endeavor to advance quality assessment and reproducibility in light microscopy

    Boehm, U.; Nelson, G.; Brown, C. M.; Bagley, Steve; Bajcsy, P.; Bischof, J.; Dauphin, A.; Dobbie, I. M.; Eriksson, J. E.; Faklaris, O.; et al. (2021)
  • Comparative performance of predictors of death from thin (≤1.0 mm) melanoma

    Claeson, M.; Baade, P.; Marchetti, M.; Brown, S.; Soyer, H. P.; Smithers, B. M.; Green, Adèle C; Whiteman, D. C; Khosrotehrani, K.; Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia. (2021)
    Despite overall favourable prognosis,1 thin (≤1.0 mm) cutaneous melanoma account for 23% of melanoma deaths in the high-risk general population of Queensland, Australia (2005-2009), because of the sheer volume of disease.2 The prospect of adjuvant systemic therapy has increased the focus on identifying patients with thin melanoma who are at high risk of death, such as through gene expression profiling (GEP), sentinel lymph node biopsy (SLNB), or prognostic models.3-5.
  • DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells

    Cueto, F. J.; Del Fresno, C.; Brandi, P.; Combes, A. J.; Hernández-García, E.; Sánchez-Paulete, A. R.; Enamorado, M.; Bromley, Christian P; Gomez, M. J.; Conde-Garrosa, R.; et al. (2021)
    Background: Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. Methods: B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. Results: Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. Conclusion: DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.

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