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Mutations in the Kras oncogene are present in approximately 25% of tumors, while defective primary cilium can either promote or suppress specific cancer types. In the present study, we investigated whether mutations in Kras and genes important for primary cilium formation could collaboratively contribute to pancreatic cancer. Using mouse models, we found the presence of collaboration when these mutations were induced in the pancreas during embryogenesis, whereas no collaboration was observed when they were induced after birth. These results help to understand why mutations in ciliary genes do not appear in the mutational landscape of human pancreatic cancer.

High T‐cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T‐cell responses in CRC could inspire novel therapeutic approaches to achieve broader immunotherapy responsiveness. Here, we investigated T cell‐suppressive properties of different myeloid cell types in an inducible colon tumor mouse model. The most potent inhibitors of T‐cell activity were tumor‐infiltrating neutrophils. Gene expression analysis and combined in vitro and in vivo tests indicated that T‐cell suppression is mediated by neutrophil‐secreted metalloproteinase activation of latent TGFβ. CRC patient neutrophils similarly suppressed T cells via TGFβ in vitro, and public gene expression datasets suggested that T‐cell activity is lowest in CRCs with combined neutrophil infiltration and TGFβ activation. Thus, the interaction of neutrophils with a TGFβ‐rich tumor microenvironment may represent a conserved immunosuppressive mechanism in CRC. Synopsis Neutrophil infiltration is a conserved characteristic in human and mouse colon tumors, and is initiated during the formation of early adenomas. Neutrophils contribute to an immune‐suppressive tumor microenvironment through the secretion of MMPs, which activate latent TGFβ stored in the tumor stroma. Inflammatory T cells counteracted mouse colon adenoma formation at the earliest stage, but were excluded during disease progression. In contrast, neutrophils infiltrated early‐stage as well as established mouse colon adenomas, where they suppressed inflammatory T cells through matrix metalloproteinase‐mediated activation of latent TGFβ stored in the tumor microenvironment. In mice, targeting neutrophils or neutrophil‐mediated TGFβ activation counteracted colon adenoma formation and promoted tumor T cell activity. Similar to mouse tumors, human colon carcinomas were frequently infiltrated with neutrophils. Human colon carcinomas with high neutrophil infiltration and TGFβ activation had the lowest T cell infiltration. Graphical Abstract Neutrophil infiltration is a conserved characteristic in human and mouse colon tumors, and is initiated during the formation of early adenomas. Neutrophils contribute to an immune‐suppressive tumor microenvironment through the secretion of MMPs, which activate latent TGFβ stored in the tumor stroma.

In the era of precision medicine, the tumor microenvironment (TME) of esophageal cancer needs further insight, to identify unfavorable biology leading to poor outcomes. This study analyzed the TME of esophageal cancer in relation to clinicopathologic parameters, and neoadjuvant treatment. A series of patients operated for esophageal cancer with curative intent between 01.2009 and 12.2021 were included. Initial biopsies and surgical specimens of all patients underwent immunohistochemical analysis, to detect the immune infiltrate markers CD3+, CD8, CD163, CD68, PD-L1 and FoxP3+. The CPS score was used for PD-L1 quantification, whereas the Mandard regression grade (TRG) assessed pathologic response to neoadjuvant treatment (NAT). Continuous variables were compared with the Mann-Whitney-U test, and categorical ones with the Chi-2 test; paired-data tests were used when appropriate. Significance threshold was set at p  < 0.05. Overall, 68 patients (82.4% males, mean age 62.4±9.4 years, 79.4% adenocarcinoma) were included. TME in smokers had lower M2-like (CD163+, p  = 0.010) and total macrophages (CD68+, p  = 0.001), but similar CD163/68 ratio and T-cells as non-smokers. Squamous cell cancer compared to adenocarcinoma showed lower M2-like macrophages ( p  = 0.023) and T-cell infiltration ( p  = 0.006). NAT increased macrophages in the TME, while depleting Treg/FoxP3 + cells. Poor responders to NAT had similar baseline TME characteristics as complete responders, but they displayed higher total macrophage count (CD68+) after NAT ( p  = 0.026). In the present series, the TME of active smokers and patients with squamous cell cancer had a significantly reduced M2-like macrophage infiltration. Neoadjuvant treatment recruited macrophages and T-cells in the TME, but interestingly, an increased macrophage count upon final histology was related to poor response to treatment. The present study provides valuable insight to the TME composition of esophageal cancer and its modification after NAT, however, further studies are needed to assess the exact functional role of TME elements, and their impact on clinical outcomes.

Human Papillomaviruses (HPV) are highly prevalent in the sexually active populations, with a significant burden in terms of health and psychological cost in all class ages. High-risk (HR) HPV genotypes are associated with anogenital dysplasia and cancers, and anal HPV-induced cancer is increasingly observed in women. The interactions of HPV genotype's between the anus and the cervix, and the subsequent occurrence of dysplasia remains unclear. This clinical study set out to test the hypothesis that risk factors for anal HR-HPV and dysplasia may differ in women with or without cervical dysplasia or in HIV-positive women. Cervical and anal HPV genotypes and cytology testing will be performed prospectively in a cohort of women recruited in a tertiary university hospital in Switzerland. Women will be allocated to three groups: 1) normal previous cervical smear; 2) high-grade cervical dysplasia (H-SIL) at previous cervical smear; 3) HIV+, independently of previous cervical smear result. General inclusion criteria comprised the followings: Female-Age > = 18 years; Satisfactory understanding of French; No objection to HIV testing. Specific inclusion criteria are: Group 1, no past or current gynecological dysplasia and HIV negative; Group 2, Gynecological dysplasia (H-SIL) or carcinoma in situ demonstrated by histology (vulvar, vaginal or cervical) and HIV negative; Group 3: HIV-positive (regardless of viremia or CD4 count) with or without gynecological dysplasia. General exclusion criteria are: Pregnancy; History of anal dysplasia/cancer; Status after pelvic radiotherapy; Absence of anus and anal canal. Estimated prevalences of anal dysplasia are: in group 1, 1% (0-2%); in group 2, 15% (5-27%), and in group 3, 30% (19-45%). With a 10% margin error, a sample size of 120 women per group is required to reach 90% power for detecting statistical significance (unilateral [alpha] error of 5%). The primary endpoint is the prevalence of anal and cervical dysplasia, and description of the respective HPV genotypes in each group. The results of this study could improve the standard of screening of cervical and anal dysplasia in women through evidence of concomitant presence of HPV's and/or dysplasia in anus or cervix to support vaccination for instance. Beginning of recruitment started in September 2016. Results should be presented in end of 2022. Preliminary analysis for first 100 patients reveals that the mean age of the population is 39.6 (± 10.9) years with mean age of first sexual intercourse of 18.5 (± 3.9) years. In this cohort, 12% are vaccinated and 38% having had anal intercourse. Overall, 43% of the studied population had cervical HR-HPV in the studied population, and 53% had normal cytology. Anal LR HPV and HR HP were found in 27.6% and 38.4% of all patients respectively. Eighty percent had normal anal cytology. Groups 1,2 and 3 had a significant difference in terms of age, gestity, parity, age of first sexual intercourse, systematic use of condom, number of cervical LR HPV and HR HPV and abnormal cervical cytologies.

Despite the promising therapeutic effects of immune checkpoint blockade (ICB), most patients with solid tumors treated with anti-PD-1/PD-L1 monotherapy do not achieve objective responses, with most tumor regressions being partial rather than complete. It is hypothesized that the absence of pre-existing antitumor immunity and/or the presence of additional tumor immune suppressive factors at the tumor microenvironment are responsible for such therapeutic failures. It is therefore clear that in order to fully exploit the potential of PD-1 blockade therapy, antitumor immune response should be amplified, while tumor immune suppression should be further attenuated. Cancer vaccines may prime patients for treatments with ICB by inducing effective anti-tumor immunity, especially in patients lacking tumor-infiltrating T-cells. These \"non-inflamed\" non-permissive tumors that are resistant to ICB could be rendered sensitive and transformed into \"inflamed\" tumor by vaccination. In this article we describe a clinical study where we use pancreatic cancer as a model, and we hypothesize that effective vaccination in pancreatic cancer patients, along with interventions that can reprogram important immunosuppressive factors in the tumor microenvironment, can enhance tumor immune recognition, thus enhancing response to PD-1/PD-L1 blockade. We incorporate into the schedule of standard of care (SOC) chemotherapy adjuvant setting a vaccine platform comprised of autologous dendritic cells loaded with personalized neoantigen peptides (PEP-DC) identified through our own proteo-genomics antigen discovery pipeline. Furthermore, we add nivolumab, an antibody against PD-1, to boost and maintain the vaccine's effect. We also demonstrate the feasibility of identifying personalized neoantigens in three pancreatic ductal adenocarcinoma (PDAC) patients, and we describe their optimal incorporation into long peptides for manufacturing into vaccine products. We finally discuss the advantages as well as the scientific and logistic challenges of such an exploratory vaccine clinical trial, and we highlight its novelty.

Background The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined. Results The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1 -mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1 -mutant tumors were more often bilateral (odds ratio 2.75), while KRAS -mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P  < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

Background Most ovarian cancer patients are diagnosed at a late stage with 85% of them relapsing after surgery and standard chemotherapy; for this reason, new treatments are urgently needed. Ovarian cancer has become a candidate for immunotherapy by reason of their expression of shared tumor-associated antigens (TAAs) and private mutated neoantigens (NeoAgs) and the recognition of the tumor by the immune system. Additionally, the presence of intraepithelial tumor infiltrating lymphocytes (TILs) is associated with improved progression-free and overall survival of patients with ovarian cancer. The aim of active immunotherapy, including vaccination, is to generate a new anti-tumor response and amplify an existing immune response. Recently developed NeoAgs-based cancer vaccines have the advantage of being more tumor specific, reducing the potential for immunological tolerance, and inducing robust immunogenicity. Methods We propose a randomized phase I/II study in patients with advanced ovarian cancer to compare the immunogenicity and to assess safety and feasibility of two personalized DC vaccines. After standard of care surgery and chemotherapy, patients will receive either a novel vaccine consisting of autologous DCs pulsed with up to ten peptides (PEP-DC), selected using an agnostic, yet personalized, epitope discovery algorithm, or a sequential combination of a DC vaccine loaded with autologous oxidized tumor lysate (OC-DC) prior to an equivalent PEP-DC vaccine. All vaccines will be administered in combination with low-dose cyclophosphamide. This study is the first attempt to compare the two approaches and to use NeoAgs-based vaccines in ovarian cancer in the adjuvant setting. Discussion The proposed treatment takes advantage of the beneficial effects of pre-treatment with OC-DC prior to PEP-DC vaccination, prompting immune response induction against a wide range of patient-specific antigens, and amplification of pre-existing NeoAgs-specific T cell clones. Trial registration This trial is already approved by Swissmedic (Ref.: 2019TpP1004) and will be registered at http://www.clinicaltrials.gov before enrollment opens.

Infection with the hepatitis E virus (HEV) is one of the main causes of acute hepatitis worldwide. Given that, the histopathology of hepatitis E is relatively poorly characterized, and it is unclear what exactly determines its remarkable variability. The aim of our study was a systematic analysis of hepatitis E histology, especially with regard to the clinical setting. Fifty-two liver samples (48 biopsies, 1 liver explant, 3 autopsy livers) from 41 patients with molecularly proven hepatitis E (28 HEV genotype (gt) 3, three gt 1, one gt 4 and 9 undetermined gt) were systematically evaluated for 33 histopathologic features. Following one approach, the biopsies were assigned to one of five generic histologic patterns. In another approach, they were subjected to hierarchical clustering. We found that 23/41 (56%) patients were immunocompromised, whereas 18 (44%) had no known immunosuppression. Five patients (12%) had pre-existing liver disease (LD). The histopathologic spectrum ranged from almost normal to acute, chronic, and steato-hepatitis to subtotal necrosis, and was thus distributed across all five generic patterns. Hierarchical clustering, however, identified three histopathologic clusters (C1–C3), which segregated along the immune status and pre-existing LD: C1 comprised mostly patients with pre-existing LD; histology mainly reflected the respective LD without pointing to the additional hepatitis E. C2 comprised mostly immunocompetent patients; histology mainly displayed florid hepatitis. C3 comprised mostly immunocompromised patients; histology mainly displayed smoldering hepatitis. Accordingly, C1–C3 differed markedly with respect to their clinical and histopathologic differential diagnoses. Hierarchical clustering suggests three groups with distinct histopathologies, indicating biologically different manifestations of hepatitis E. The association of histopathologic changes with the patient's immune status and pre-existing LD plausibly explains the diversity of hepatitis E histopathology, and suggests that these factors are the crucial underlying determinants. We expect our results to improve patient management by guiding the clinico-pathologic diagnosis of hepatitis E.

Background Most studies on tumour progression from precursor lesion toward gallbladder adenocarcinoma investigate lesions sampled from distinct patients, providing an overarching view of pathogenic cascades. Whether this reflects the tumourigenic process in individual patients remains insufficiently explored. Genomic and epigenomic studies suggest that a subset of gallbladder cancers originate from biliary intraepithelial neoplasia (BilIN) precursor lesions, whereas others form independently from BilINs. Spatial transcriptomic data supporting these conclusions are missing. Moreover, multiple areas with precursor or adenocarcinoma lesions can be detected within the same pathological sample. Yet, knowledge about intra-patient variability of such lesions is lacking. Methods To characterise the spatial transcriptomics of gallbladder cancer tumourigenesis in individual patients, we selected two patients with distinct cancer aetiology and whose samples simultaneously displayed multiple areas of normal epithelium, BilINs and adenocarcinoma. Using GeoMx digital spatial profiling, we characterised the whole transcriptome of a high number of regions of interest (ROIs) per sample in the two patients (24 and 32 ROIs respectively), with each ROI covering approximately 200 cells of normal epithelium, low-grade BilIN, high-grade BilIN or adenocarcinoma. Human gallbladder organoids and cell line-derived tumours were used to investigate the tumour-promoting role of genes. Results Spatial transcriptomics revealed that each type of lesion displayed limited intra-patient transcriptomic variability. Our data further suggest that adenocarcinoma derived from high-grade BilIN in one patient and from low-grade BilIN in the other patient, with co-existing high-grade BilIN evolving via a distinct process in the latter case. The two patients displayed distinct sequences of signalling pathway activation during tumour progression, but Semaphorin 4 A ( SEMA4A ) expression was repressed in both patients. Using human gallbladder-derived organoids and cell line-derived tumours, we provide evidence that repression of SEMA4A promotes pseudostratification of the epithelium and enhances cell migration and survival. Conclusion Gallbladder adenocarcinoma can develop according to patient-specific processes, and limited intra-patient variability of precursor and cancer lesions was noticed. Our data suggest that repression of SEMA4A can promote tumour progression. They also highlight the need to gain gene expression data in addition to histological information to avoid understimating the risk of low-grade preneoplastic lesions.

BackgroundImmune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD.MethodsWe systematically compared liver irAEs with AILD, namely autoimmune hepatitis (AIH) and primary biliary cholangitis, regarding their clinical, laboratory, and histological features.ResultsTwenty-seven patients with liver irAEs (ICI group) and 14 patients with AILD were identified. We observed three distinct ICI-induced histological liver injury patterns: hepatitic (52%), cholangitic (19%), and mixed (29%). When comparing the ICI and AILD groups, centrilobular injury as well as granuloma formation were more prevalent in the former (p=0.067 and 0.002, respectively). CD4+/CD8+ T cell ratios were heterogeneous between the two groups, without statistically significant difference but with a trend toward increased CD8+ T cells among hepatitic irAEs as compared with AIH. Pattern of liver function test alteration was predictive for the type of irAEs but did not correlate with histological severity.ConclusionsLiver irAEs have broad clinical, laboratory and histological presentations. Histological features of irAEs and AILD are distinct, likely underpinning their different immunological mechanisms.