Intraepithelial CD15 infiltration identifies high grade anal dysplasia in people with HIV

Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. The identification of local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. We performed a study of 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. In a test prospective cohort (N=54), in addition to histological examination, we assessed multiple immune subsets by flow cytometry. Selected molecules were further evaluated by immunohistochemistry in a validation retrospective cohort (N=47). Pathological samples were characterized by the presence of Resident Memory T cells with low expression of CD103 and by changes in the Natural Killer cell subsets, affecting residency and activation. Furthermore, potentially immune suppressive subsets, including CD15+ CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry confirmed the association between the presence of CD15 in the epithelium and SIL diagnosis, with a sensitivity of 80% and specificity of 71% (AUC 0.762) for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune suppressive subsets characterizes pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was primarily supported by grants from the Spanish Health Institute Carlos III (ISCIII, PI16/00736 and PI20/00160), co-funded by ERDF/ESF, A way to make Europe/Investing in your future. This work was additionally supported in part by the Spanish AIDS network Red Tematica Cooperativa de Investigacion en SIDA (RD16/0025/0007), the Fundacio La Marato TV3 (201814-10FMTV3) and the Gilead fellowships GLD18/00008. M.J.B is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). N.M. was supported by a Ph.D. fellowship from the VHIR. The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Informed consent for sample collection and use of information available in the medical records was obtained from all patients included. This study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (PR(AG)240/2014) of the University Hospital Vall Hebron (HUVH, Barcelona, Spain). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript. [1]: pending:yes