Roe, D. J. | bioRxiv Science

bioRxiv2024

Distinct sets of molecular characteristics define tumor-rejecting neoantigens

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

immunology↗

bioRxiv2023

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

cancer biology↗

bioRxiv2017

Lack of Evidence that Ursodeoxycholic Acid’s Effects on the Gut Microbiome Influence Colorectal Adenoma Risk

ObjectiveWe previously reported that Ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduces risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colon cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies.\n\nDesignUsing banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal neoplasia, we compared change in the microbiome composition after 3 years intervention in a subset of participants randomized to 8-10 mg/kg of body weight UDCA (n=198) to placebo (n=203). UDCA effects on the microbiome, sex and adenoma outcome were investigated.\n\nResultsStudy participants randomized to UDCA experienced compositional changes in their microbiome that were statistically more similar to other individuals in the UDCA arm than to those in the placebo arm. This change reflected an UDCA-associated shift in microbial community distance metrics (P <0.001), independent of sex, with no evidence of UDCA effect on microbial richness (P > 0.05). These UDCA-associated shifts in microbial community distance metrics from baseline to end-of-study were not associated with risk of any or advanced adenoma (all P> 0.05) in men or women.\n\nConclusionDespite a large sampling of randomized clinical trial participants, daily UDCA use only modestly influenced the relative abundance of microbial species in stool with no evidence for effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk.\n\nSUMMARYO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIUrsodeoxycholic acid (UDCA) is a therapeutic bile acid used in the treatment of primary biliary cirrhosis (PBC) and investigated for anti-cancer activity in the colon\nC_LIO_LIIn humans, UDCA is produced in the colon from the conjugation of primary bile acids by intestinal bacteria\nC_LIO_LIIntestinal bacteria play a critical role in human intestinal health and disease including a hypothesized role in the development of colorectal cancer.\nC_LIO_LIUDCA was found to reduce the risk of more advanced colorectal adenoma with effects present in men but not women.\nC_LIO_LITherapeutic UDCA was recently shown to reduce the extent of bacterial dysbiosis in patients with PBC\nC_LI\n\nWhat are the new findings?O_LIAmong a population of patients with colorectal adenoma, low dose oral UDCA taken daily produced modest changes in fecal bacterial composition\nC_LIO_LIUDCA associated changes in the gut microbiome were similar in men and women.\nC_LIO_LIUDCA associated changes in the gut micobiome were not associated with risk of any or advanced colorectal adenoma in the patient population.\nC_LI\n\nHow might it impact on clinical practice in the foreseeable future?O_LIThese findings confirm effects of oral UDCA on the microbiome that may be beneficial for patients with PBC.\nC_LIO_LIThese findings suggest that the anti-cancer effects of UDCA for colorectal adenoma prevention are not due to major effects of UDCA on the gut microbiome.\nC_LI

cancer biology↗