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T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8 + T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti–programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.

Background Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. Methods These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. Results Study 1280.1 involved 61 patients (part I: xentuzumab 10–1800 mg weekly, n  = 48; part II: 1000 mg weekly, n  = 13); study 1280.2, 64 patients (part I: 10–3600 mg three-weekly, n  = 33; part II: 1000 mg weekly, n  = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. Conclusions Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. Clinical trial registration NCT01403974; NCT01317420.

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 ( IGF2 ) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2 -overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2 -overexpressing CRC patients.

Xentuzumab is an insulin‐like growth factor (IGF) ligand‐neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ≥20 y old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/wk. Dose escalation used a 3 + 3 design with dose de‐escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics, and anti‐tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/wk [n = 6]; 1000 mg/wk [n = 3]; 1400 mg/wk [n = 6]). There were no dose‐limiting toxicities at any dose; the MTD of xentuzumab was not reached. Xentuzumab 1000 mg/wk was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/wk in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug‐related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decrease, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF‐1 and IGF‐2 levels increased and bioactive IGF levels decreased from baseline to 24 h after the first infusion in cycle 1. Partial response was observed in 2 (9.5%) patients with desmoid‐type fibromatosis. Disease control was achieved in 6 (28.6%) patients (median duration 42.4 mo). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti‐tumor activity. This study was registered with www.clinicaltrials.gov (NCT02145741). This phase 1 study assessed the safety and anti‐tumor activity of xentuzumab in 21 Japanese patients with solid tumors. Treatment was generally well tolerated with no significant changes in blood glucose levels and no drug‐related grade ≥3 adverse events. Two patients (9.5%) had a partial response and disease control was achieved in a total of 6 patients (28.6%); both patients with partial responses and 2 patients with stable disease had sarcomas.

Background: Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways. Methods: Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR. Results: IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration. Conclusions: IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies.

Summary Purpose This Phase I, open-label, single-arm, dose-escalation study aimed to evaluate the safety and tolerability of the insulin-like growth factor (IGF-I/II) neutralizing antibody, MEDI-573, in Japanese patients with advanced solid tumours refractory to standard therapy or for which no standard therapy exists. The pharmacokinetics, pharmacodynamics and antitumour activity of MEDI-573 were also evaluated. Methods Three cohorts of patients received MEDI-573 in escalating order: cohort 1, 5 mg/kg on Day 1, 8 and 15; cohort 2, 15 mg/kg on Day 1, 8 and 15; cohort 3, 45 mg/kg on Day 1, of 21-day cycles. Results Ten patients who received at least one dose of MEDI-573 were evaluated. The median number of treatment cycles was 2.0 (range 1–6) and the median number of MEDI-573 doses received was 4.0 (range 1–17). The most commonly reported drug-related adverse events were fatigue ( n  = 2 patients), pyrexia ( n  = 2), diarrhoea ( n  = 2) and electrocardiogram QT prolongation ( n  = 2). No patients experienced a dose-limiting toxicity. Pharmacokinetics of MEDI-573 were linear with a dose-dependent increase. There were no complete or partial responses; four patients had an overall best response of stable disease. Conclusions MEDI-573 is well tolerated at the doses investigated.

Fetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific P promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7,264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T-cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the environment is a contributory factor.

Many growth factors and cytokines are immobilized on the extracellular matrix (ECM) by binding to glycosaminoglycans and are stored in an inactive form in the cellular microenvironment. However, the mechanisms of ECM‐bound growth factor or cytokine activation have not been well documented. We showed that the insulin‐like growth factor type‐1 receptor (IGF‐1R) was rapidly phosphorylated after the addition of matrix metalloproteinase (MMP)‐7 to a serum‐starved human colon cancer cell line (HT29) and that phosphorylation was completely inhibited by an IGF‐II neutralizing antibody. In the ECM of this cell line, IGF‐II and IGF binding protein (BP)‐2 coexisted, but IGFBP‐2 disappeared from the ECM fraction after treatment with MMP‐7 or heparinase III. On the other hand, in a cell line in which IGF‐1R was overexpressed, IGF‐1R was phosphorylated by supernatant from the MMP‐7‐treated ECM fraction of HT29 but not by that from a heparinase‐III‐treated ECM fraction. We also demonstrated that MMP‐7 degrades IGFBP‐2 in vitro at three cleavage sites (peptide bonds E151–L152, G175–L176 and K181–L182), which have not been documented previously. Taken together, these results demonstrate that MMP‐7 generates bioactive IGF‐II by degrading the IGF‐II/IGFBP‐2 complex binding to heparan sulfate proteoglycan in the ECM, resulting in IGF‐II‐induced signal transduction. This evidence indicates that some ECM‐associated growth factors enhance their ability to bind to their receptors by some proteases in the tumor microenvironment. This mechanism of action (‘protease‐triggered matricrine’) represents an attractive model for understanding ECM–tumor interactions. (Cancer Sci 2007; 98: 685–691)

Before being able to react against infectious non-self-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins, and this critical process essentially takes place in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β cell reactive effector T cells and a deficiency of β cell-specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called \"negative/tolerogenic self-vaccination\", is currently developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of negative self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases.

The semiquantitative reverse transcription polymerase chain reaction was employed to detect the expression of transforming growth factor beta (TGF-beta) and insulin-like growth factor (IGF) in complete hydatidiform mole, normal first-trimester villi, the normal term placenta (after vaginal/abdominal deliver) and the preeclamptic placenta at term. The expression of IGF-I mRNA was seen in all five tissues, but its level was much lower in the term placental tissues with preeclampsia than in other tissues. The content of IGF-I mRNA in villous tissues from molar pregnancy was slightly higher than in normal first-trimester villi. IGF-II mRNA was detected at similar levels in all three sorts of term placental tissues. However, the expression level of IGF-II mRNA in tissues of complete molar pregnancy was significantly lower than in normal first-trimester villi. TGF-beta(3) was found expressed in all five tissues, while TGF-beta(1) and TGF-beta(2) mRNA were not detected. Compared to the normal first-trimester villi, the expression of TGF-beta(3) in complete hydatidiform molar tissues was comparatively higher. Furthermore, the expression levels of TGF-beta(3) in the preeclamptic placenta and the normal placenta after cesarean birth were higher than in the placenta after vaginal delivery. We concluded that, the change of TGF-beta and IGF expression in placental tissues might be involved in the development of trophoblastic diseases of pregnancy.