Natural killer cell educating KIR/HLA combinations impact survival in anti-PD-L1 treated cancer patients

Natural killer (NK) cells are educated through the binding of killer immunoglobulin like receptors (KIR) to human leukocyte antigen (HLA) proteins, but it is unknown whether the presence of these highly diverse KIR/HLA interactions influence responses to immunotherapy in solid tumors. We report herein two observations that shed light on NK cell function and abundance in anti-tumor immune responses. In patients with non-small cell lung cancer treated with anti-PD-L1 therapy, we found that individuals carrying HLA-C1 and HLA-Bw4 alleles and the genes coding for their receptors KIR2DL3 and KIR3DL1 showed improved overall survival (OS). Combined with our second finding that NK cell infiltration was independently associated with improved OS, our findings have important implications for precision medicine approaches and the development of NK cell-based therapies. ### Competing Interest Statement DR, HR, ZK, PD, RM, GSC, MIM, IM, and CH are employees of Genentech / Roche. JH was an employee of Genentech / Roche. JC and MLA were employees of Genentech / Roche, and are currently employees of Human Immunology Biosciences. ### Funding Statement This study did not receive any funding. ### 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: Patients included in the present study signed an optional Research Biosample Repository (RBR) Informed Consent Form (ICF) and provided whole blood samples. By signing, patients provided informed consent for analysis of inherited and non-inherited genetic variation from whole blood samples. Ethics Committees (EC) and Institutional Review Boards (IRB) in each country and each study site for each clinical trial approved the clinical trial protocol, the main study ICF, and the RBR ICF. All EC and IRB forms are provided in the supplementary data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Qualified researchers may request access to individual patient data used in this study through Roche's data sharing platforms in accordance with the Global Policy on Sharing of Clinical Study Information: [http://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm][1]. To ensure compliance with legal, data retention, and patient confidentiality obligations in the informed consent forms (ICF), the whole-genome sequencing data collected (in VCF or BAM/FASTQ formats) cannot be hosted on a public, controlled access repository and will be made available to individual requesters on completion of a data sharing agreement with Roche/Genentech. Requests for access to whole-genome sequencing data should be made to the corresponding author by email at hammer.christian{at}gene.com. The planned research with the requested data will be reviewed by the Roche Pharma Repository Governance Committee to assess its scientific merit and to ensure it is within scope of the ICF approved locally at each study site. [1]: http://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm