Correct stimulation of CD28H arms NK cells against tumor cells.

Tumor evasion has recently been associated with a novel member of the B7 family, HERV-H LTR-associating 2 (HHLA2), which is mostly overexpressed in PDL-1neg tumors. HHLA2 can either induce a costimulation signal when bound to CD28H or inhibit it by binding to KIR3DL3 on T- and NK cells. Given the broad distribution of CD28H expression on NK cells and its role, we compared two monoclonal antibodies targeting this novel NK-cell engager in this study. We show that targeting CD28H at a specific epitope not only strongly activates Ca2+ flux but also results in NK-cell activation. CD28H-activated NK cells further display increased cytotoxic activity against hematopoietic cell lines and bypass HHLA2 and HLA-E inhibitory signals. Additionally, scRNA-seq analysis of clear cell renal cancer cells revealed that HHLA2+ clear cell renal cancer cell tumors were infiltrated with CD28H+ NK cells, which could be targeted by finely chosen anti-CD28H Abs.

[18F]FDG PET/CT for predicting triple-negative breast cancer outcomes after neoadjuvant chemotherapy with or without pembrolizumab.

PURPOSE: To determine if pretreatment [18F]FDG PET/CT could contribute to predicting complete pathological complete response (pCR) in patients with early-stage triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy with or without pembrolizumab. METHODS: In this retrospective bicentric study, we included TNBC patients who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy (NAC) or chemo-immunotherapy (NACI) between March 2017 and August 2022. Clinical, biological, and pathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from the PET images. Cut-off values were determined using ROC curves and a multivariable model was developed using logistic regression to predict pCR. RESULTS: N = 191 patients were included. pCR rates were 53 and 70% in patients treated with NAC (N = 91) and NACI (N = 100), respectively (p < 0.01). In univariable analysis, high Ki67, high tumor SUVmax (> 12.3), and low TMTV (≤ 3.0 cm3) were predictors of pCR in the NAC cohort while tumor staging classification (< T3), BRCA1/2 germline mutation, high tumor SUVmax (> 17.2), and low TMTV (≤ 7.3 cm3) correlated with pCR in the NACI cohort. In multivariable analysis, only high tumor SUVmax (NAC: OR 8.8, p < 0.01; NACI: OR 3.7, p = 0.02) and low TMTV (NAC: OR 6.6, p < 0.01; NACI: OR 3.5, p = 0.03) were independent factors for pCR in both cohorts, albeit at different thresholds. CONCLUSION: High tumor metabolism (SUVmax) and low tumor burden (TMTV) could predict pCR after NAC regardless of the addition of pembrolizumab. Further studies are warranted to validate such findings and determine how these biomarkers could be used to guide neoadjuvant therapy in TNBC patients.

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents.

Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24(int)CD38(+)CD27(+)IgD(-)IgM(+/low) subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-ß1-dependent mechanisms and to suppress in vitro TNF-α secretion. Following anti-CD40 stimulation, IgD(-)IgM(+/low) B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3(+)CD4(+)CD25(+) regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3(+)CD4(+)CD25(+) regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic.

18F-fluorocholine versus 18F-fluorodeoxyglucose for PET/CT imaging in patients with suspected relapsing or progressive multiple myeloma: a pilot study.

PURPOSE: Hybrid positron emission tomography/computed tomography (PET/CT) has now become available, as well as whole-body, low-dose multidetector row computed tomography (MDCT) or magnetic resonance imaging (MRI). The radioactive glucose analogue 18F-fluorodeoxyglucose (FDG) is the most widely used tracer but has a relatively low sensitivity in detecting multiple myeloma (MM). We compared FDG with a more recent metabolic tracer, 18F-fluorocholine (FCH), for the detection of MM lesions at time of disease relapse or progression. METHODS: We analyzed the results of FDG and FCH imaging in 21 MM patients undergoing PET/CT for suspected relapsing or progressive MM. For each patient and each tracer, an on-site reader and a masked reader independently determined the number of intraosseous and extraosseous foci of tracer and the intensity of uptake as measured by their SUVmax and the corresponding target/non-target ratio (T/NT). RESULTS: In the skeleton of 21 patients, no foci were found for two cases, uncountable foci were observed in four patients, including some mismatched FCH/FDG foci. In the 15 patients with countable bone foci, the on-site reader detected 72 FDG foci vs. 127 FCH foci (+76 %), whereas the masked reader detected 69 FDG foci vs. 121 FCH foci (+75 %), both differences being significant. Interobserver agreement on the total number of bone foci was very high, with a kappa coefficient of 0.81 for FDG and 0.89 for FCH. Measurement of uptake in the matched foci that took up both tracers revealed a significantly higher median SUVmax and T/NT for FCH vs. FDG. Almost all unmatched foci were FCH-positive FDG-negative (57/59 = 97 % on-site and 56/60 = 93 % on masked reading); they were more frequently observed than matched foci in the head and neck region. CONCLUSIONS: These findings suggest that PET/CT performed for suspected relapsing or progressive MM would reveal more lesions when using FCH rather than FDG.

Consequence of the introduction of routine FCH PET/CT imaging for patients with prostate cancer: a dual centre survey.

BACKGROUND: Fluorocholine(18F) (FCH) was introduced at the beginning of April 2010 in France, Slovenia and three other EU member states for the localisation of bone metastases of prostate cancer with PET. The aim of the study was to compare the evolution of diagnostic imaging in patients with prostate cancer using a new radiopharmaceutical FCH, observed in France and in Slovenia, and to quantify the consequence of the results of new imaging modality on the detection rate of abnormal metastases and recurrences of prostate cancer. PATIENTS AND METHODS: In two centres (France/Slovenia), a survey of the number of nuclear medicine examinations in patients with prostate cancer was performed, covering 5 quarters of the year since the introduction of FCH. For each examination, the clinical and biological circumstances were recorded, as well as the detection of bone or soft tissue foci. RESULTS: Six hundred and eighty-eight nuclear medicine examinations were performed impatients with prostate cancer. Nuclear medicine examinations were performed for therapy monitoring and follow-up in 23% of cases. The number of FCH PET/CT grew rapidly between the 1(st) and 5(th) period of the observation (+220%), while the number of bone scintigraphies (BS) and fluoride(18F) PET/CTs decreased (-42% and -23% respectively). Fluorodeoxyglucose(18F) (FDG) PET/CT remained limited to few cases of castrate-resistant or metastatic prostate cancer in Paris. The proportion of negative results was significantly lower with FCH PET/CT (14%) than with BS (49%) or fluoride(18F) PET/CT (54%). For bone metastases, the detection rate was similar, but FCH PET/CT was performed on average at lower prostate-specific antigen (PSA) levels and was less frequently doubtful (4% vs. 28% for BS). FCH PET/CT also showed foci in prostatic bed (53% of cases) or in soft tissue (35% of cases). CONCLUSIONS: A rapid development of FCH PET/CT was observed in both centres and led to a higher detection rate of prostate cancer lesions.

Incidental uptake of (18)F-fluorocholine (FCH) in the head or in the neck of patients with prostate cancer.

BACKGROUND: Positron emission tomography-computed tomography (PET/CT) with (18)F-fluorocholine (FCH) is routinely performed in patients with prostate cancer. In this clinical context, foci of FCH uptake in the head or in the neck were considered as incidentalomas, except for those suggestive of multiple bone metastases. RESULTS: In 8 patients the incidental focus corresponded to a benign tumour. The standard of truth was histology in two cases, correlative imaging with MRI in four cases, (99m)Tc-SestaMIBI scintigraphy, ultrasonography and biochemistry in one case and biochemistry including PTH assay in one case. The final diagnosis of benign tumours consisted in 3 pituitary adenomas, 2 meningiomas, 2 hyperfunctioning parathyroid glands and 1 thyroid adenoma. Malignancy was proven histologically in 2 other patients: 1 papillary carcinoma of the thyroid and 1 cerebellar metastasis. CONCLUSIONS: To the best of our knowledge, FCH uptake by pituitary adenomas or hyperfunctioning parathyroid glands has never been described previously. We thus discuss whether there might be a future indication for FCH PET/CT when one such tumour is already known or suspected: to detect a residual or recurrent pituitary adenoma after surgery, to guide surgery or radiotherapy of a meningioma or to localise a hyperfunctioning parathyroid gland. In these potential indications, comparative studies with reference PET tracers or with (99m)Tc-sestaMIBI in case of hyperparathyroidism could be undertaken.

18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type.

6-Fluoro-((18)F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, (123)I-metaiodobenzylguanidine (MIBG) and (111)In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for (123)I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as small cell prostate cancer, or in emerging indications, such as metastatic NET of unknown primary (CUP-NET) or adrenocorticotropic hormone (ACTH) ectopic production. An evidence-based strategy in NET functional imaging is as yet affected by a low number of comparative studies. Then the suggested diagnostic trees, being a consequence of the analysis of present data, could be modified, for some indications, by a wider experience mainly involving face-to-face studies comparing FDOPA and (68)Ga-labelled peptides.

Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial.

Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8-99.8%] with a 2-year PFS of 75% [95% CI: 56.5-99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.

Tumor Thrombus on 18F-FDG PET/CT in Stage IV Plasmablastic Lymphoma.

ABSTRACT: A 71-year-old woman with a history of back pain and recent weight loss presented to the emergency department with hematuria. A CT scan was performed and showed left retroperitoneal mass with left renal vein thrombus extended to the vena cava. Tumor biopsy revealed plasmablastic lymphoma. Staging with 18F-FDG PET/CT scan was performed and revealed pulmonary, hepatic, and left supraclavicular lymph node extension. The left retroperitoneal mass showed intense FDG uptake and was associated with widespread tumor thrombus in the peripheral abdominal veins. Differentiating tumor thrombus from bland thrombosis has a significant impact on patient's management.

Impact of FDG PET/CT in the staging and the follow-up of anal carcinoma.

PURPOSE: The purpose of the study was to assess the diagnostic performance of positron emission tomography/computed tomography and fluorodeoxyglucose (18F) (FDG PET/CT) for the staging and the follow-up of anal carcinoma, and to evaluate the impact of FDG PET/CT on patient management. MATERIALS AND METHODS: Patients with anal carcinoma were referred to our department from October 2004 until July 2008. The diagnostic performance was evaluated on a perexamination basis and on a per-site basis, together with impact of PET/CT on patient management. The standard of truth was histology when available and, in all cases, follow-up data during at least 6 months. RESULTS: Fifty-eight FDG PET/CT performed in 44 patients were analysed­22 for initial staging and 36 during follow-up. The detection rate of non-excised tumours on initial examination was 93%. During post-treatment follow-up, FDG PET/CT had, on a per-examination basis, sensitivity for the detection of persistent or recurrent disease of 93% and specificity of 81%, and on a per-site basis, 86% and 97%, respectively. Its negative predictive value was 94% on a per-examination basis and 98% on a per-site basis. FDG PET/CT had an impact on management in nine patients out of 44 (20%), which was relevant in eight of them (89%). CONCLUSION: FDG PET/CT is an accurate imaging modality in anal cancer. It has an interesting added value during post-treatment follow-up, especially when persistence or recurrence of disease is suspected. Further studies are needed to evaluate whether surveillance by means of FDG PET/CT might have a positive impact on overall survival.

A Rare Cause of SCC Antigen Elevation: Inverted Sinonasal Papilloma.

ABSTRACT: We report the case of a 68-year-old woman who underwent 18F-FDG PET/CT for squamous cell carcinoma antigen (SCC Ag) elevation in the follow-up of a uterine cervical cancer. The examination showed an FDG-avid mass of the left nasal cavity with left maxillary sinusitis and no other site of abnormal FDG uptake. Surgical resection of the nasal polyp was performed, and pathological examination of the specimen revealed an inverted sinonasal papilloma. SCC Ag returned to normal after surgery. Inverted sinonasal papilloma is a rare cause of SCC Ag elevation, which can be depicted by 18F-FDG PET/CT.

Gallbladder Metastasis From Conjunctival Melanoma.

Malignant conjunctival melanoma is a rare tumor. A 46-year-old woman with a history of locally recurrent left conjunctival melanoma was followed by F-FDG PET/CT. Four years after the local recurrence treated by orbital exenteration, the follow-up PET/CT scan showed an incidental intense FDG uptake mass infiltrating the gallbladder associated with a low uptake of an infracentimetric pulmonary nodule. The patient was completely asymptomatic with no sign of local recurrence. Laparoscopic cholecystectomy was performed, and histopathologic findings were consistent with gallbladder metastasis of melanoma. After almost 2 years of immunotherapy, the patient is still in complete response.

18F-FDG Whole-body PET/MRI of a 30-Week Pregnant Woman With Breast Cancer Revealed Interesting Fetal Findings.

A 35-year-old 30-week pregnant woman was referred to our institution for initial staging of a triple negative invasive ductal carcinoma of the left breast. To avoid fetal radiation exposure from CT, a whole-body F-FDG PET/MRI was performed. Simultaneous acquisition of PET, T1-, T2-, and diffusion-weighted sequences revealed left axillary node extension and no distant metastases. Fetal radiation dose was estimated at 1.9 mGy. Interestingly, low fetal brain uptake and high symmetrical myocardial metabolism in both ventricles were found. Delivery was induced at 37 weeks of amenorrhea, and the patient underwent 4 cycles of neoadjuvant chemotherapy.

A Case of Sarcoidosis After Lymphoma.

We report the case of a 62-year-old woman with previous history of stage III Hodgkin lymphoma. Routine follow-up CT scan revealed 2 years after end of treatment the appearance of mediastinal nodes, suspected of lymphoma recurrence. An F-FDG PET/CT was performed showing hypermetabolic mediastinal lymph nodes with diffuse symmetric osteomedullar hypermetabolism of pelvis and scapulae. In the hypothesis of either recurrence or multisystemic inflammatory disorder, bone marrow and lymph node biopsies were performed, revealing the presence of noncaseating epithelioid cell granulomas, leading to the diagnosis of multisystemic sarcoidosis. This case illustrates the sarcoidosis-lymphoma syndrome.

18F-Choline PET/CT Imaging for Intracranial Hemangiopericytoma Recurrence.

We report the case of a 50-year-old man, with previous history of grade 3 intracranial hemangiopericytoma with initial complete surgical resection, addressed for local recurrence. Surgical revision performed 18 months after initial surgery allowed only partial resection, leaving residual disease along the optic nerve. Complementary radiotherapy with proton was decided. F-FDG PET/CT and F-choline PET/CT were both performed for treatment planning. F-FDG PET showed no uptake of the residual tumor, whereas F-choline depicted highly metabolic residual disease uptake with excellent delineation of local recurrence. F-choline PET/CT appears as a useful PET tracer for hemagiopericytoma imaging.

Primary and Secondary Breast Angiosarcoma: FDG PET/CT Series.

Breast angiosarcoma is a rare and aggressive tumor. The role of F-FDG PET/CT in breast angiosarcoma is poorly known. We report a series of 13 lesions in 11 patients with histologically proven primary or secondary breast angiosarcoma who underwent FDG PET/CT at the initial assessment in our institution. All breast lesions showed FDG avidity. Visually and statistically, we observed a significant difference of SUVmax uptake foci between primary and secondary breast angiosarcoma (Wilcoxon test P < 0.0046) and a significantly poorer prognosis for high SUVmax than those with low SUVmax (P = 0.049) regardless of primary or secondary origins.

18F-fluorocholine PET/CT in patients with occult biochemical recurrence of prostate cancer: Detection rate, impact on management and adequacy of impact. A prospective multicentre study.

AIM: To prospectively evaluate the clinical impact and the diagnostic performance of FCH-PET/CT in patients with occult biochemical recurrence of prostate cancer (PCa). MATERIALS AND METHODS: Results of 179 patients (mean PSA = 7.5ng/mL) with negative/inconclusive results of pelvic-MRI and of bone-scintigraphy were analysed. To determine the impact of FCH-PET/CT on diagnostic thinking and on patient management, the referring physicians prospectively filled-in a 1st and 2nd questionnaire related to patient's planned management before and after FCH-PET/CT. Based on data from a 6-month follow-up after FCH-PET/CT, an independent assessor blinded to results of FCH-PET/CT determined the adequacy of management changes motivated by FCH-PET/CT. RESULTS: FCH-PET/CT localised foci evocative of recurrent PCa in 59% (105/179) of patients. Results of FCH-PET/CT motivated a change in scheduled patient management in 56% (100/179) of patients; which was considered as adequate in 89% (89/100) of patients. FCH-PET/CT also led to the detection of lung cancer in two patients. CONCLUSION: FCH PET/CT is a powerful tool to localise the sites of occult biochemical recurrence of PCa, leading to an adequate management change in half of patients.

Influence of CA 15-3 blood level and doubling time on diagnostic performances of 18F-FDG PET in breast cancer patients with occult recurrence.

AIM: To evaluate the influence of CA 15-3 blood level and doubling time on diagnostic performances of 18F-FDG PET in breast cancer patients with occult recurrence. MATERIALS AND METHODS: Thirty-five 18F-FDG PET examinations in 32 patients with CA 15-3 blood level above the normal range, and negative conventional imaging within 3 months before PET examination were included in this retrospective study. PET examinations were reviewed blindly by two experienced nuclear medicine physicians who were unaware of any clinical, biological or radiological information. CA 15-3 assays performed prior to the PET examinations and all using the same technique were collected and used for doubling time calculation if (1) no therapeutic modification occurred in the meantime, and (2) the delay between assays was less than 6 months. RESULTS: Median CA 15-3 blood levels were higher in the positive PET group (100 U x ml(-1)) than in the negative group (65 U x ml(-1)) (P=0.04). The likelihood of depicting recurrence was higher in patients with a short doubling time (<180 days) (P=0.05), a CA 15-3 blood level >60 U x ml(-1) (P=0.05), and when a short doubling time was associated with a CA 15-3 blood level >60 U x ml(-1) (P=0.03). CONCLUSIONS: The likelihood of depicting recurrence was influenced by CA 15-3 blood level and doubling time. Further studies are required to confirm that selections of patients based on those criteria could improve the sensitivity of positron emission tomography in the detection of breast cancer recurrence, particularly in the case of low CA 15-3 blood level.

[Clinical usefulness of positron emission tomography in prostate cancer]. / Utilité clinique de la tomographie par émission de positons dans le cancer de la prostate.

In prostate cancer, use of FDG, the radiopharmaceutical currently most widely used in oncology, is limited to the most aggressive cancers and, in the absence of another tracer, to attempting to localise occult recurrences detected biochemically (elevated PSA serum levels). Four other PET tracers are currently suggested in various situations of prostate cancer development: for guiding biopsies, for diagnosis and staging of the primary cancer and of local or metastatic recurrences, especially in bone, and for localizing occult biochemical recurrence. This article is illustrated by cases summarising our experience with fluoromethylcholine-(18F) and PET/CT. They cover a wide spectrum of clinical settings: localisation of intraprostatic neoplastic lesions, initial staging, monitoring treatment by ultrasound, detection of occult recurrences and characterisation of images on conventional imaging modalities, which are questionable or difficult to interpret.

Cell-surface C-type lectin-like receptor CLEC-1 dampens dendritic cell activation and downstream Th17 responses.

Dendritic cells (DCs) represent essential antigen-presenting cells that are critical for linking innate and adaptive immunity, and influencing T-cell responses. Among pattern recognition receptors, DCs express C-type lectin receptors triggered by both exogenous and endogenous ligands, therefore dictating pathogen response, and also shaping T-cell immunity. We previously described in rat, the expression of the orphan C-type lectin-like receptor-1 (CLEC-1) by DCs and demonstrated in vitro its inhibitory role in downstream T helper 17 (Th17) activation. In this study, we examined the expression and functionality of CLEC-1 in human DCs, and show a cell-surface expression on the CD16- subpopulation of blood DCs and on monocyte-derived DCs (moDCs). CLEC-1 expression on moDCs is downregulated by inflammatory stimuli and enhanced by transforming growth factor ß. Moreover, we demonstrate that CLEC-1 is a functional receptor on human moDCs and that although not modulating the spleen tyrosine kinase-dependent canonical nuclear factor-κB pathway, represses subsequent Th17 responses. Interestingly, a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and is associated with a higher level of interleukin 17A (IL17A). Importantly, using CLEC-1-deficient rats, we showed that disruption of CLEC-1 signaling led to an enhanced Il12p40 subunit expression in DCs, and to an exacerbation of downstream in vitro and in vivo CD4+ Th1 and Th17 responses. Collectively, our results establish a role for CLEC-1 as an inhibitory receptor in DCs able to dampen activation and downstream effector Th responses. As a cell-surface receptor, CLEC-1 may represent a useful therapeutic target for modulating T-cell immune responses in a clinical setting.