Immune evasion from natural killer cells by non small cell lung carcinoma

Although treatment of patients with non small cell lung carcinoma has improved over the last decade – most notably with checkpoint-based immunotherapies – the majority of patients relapse with resistant and disseminated disease. This highlights that current treatments likely incite incomplete clearance, and may allow outgrowth of escape mutants. The success of cancer therapies, especially checkpoint blockade, relies on collaboration with the immune system. Complete and durable control of NSCLC will require continued activation and activity of the immune system, in a way that is sufficiently dynamic to recognize and control evolving tumors. Anti-PD1/PD-L1 immunotherapy is thought to function by relieving immunosuppression of lymphocytes; in addition to T cells, NK cells can be inhibited through PD-1/PD-L1 interactions and rescued by checkpoint inhibition. PD-1/PD-L1 therapy does not universally result in complete control of NSCLC, and tumor genomic analyses have revealed that relapsing tumors lack HLA expression, owing to alterations in the genes and/or expression of members of the HLA processing and presentation pathways. We find that both PD-L1 and HLA expression on NSCLC are highly dynamic, suggesting that the role of NK cells in controlling NSCLC might vary over the course of treatment and evolution of the tumor. Natural killer (NK) cells are important mediators of cancer surveillance and contributors to treatment efficacy, but understudied as targets to maximize the impact of immunotherapy. NK cells' anticancer functions are various and include direct lysis of transformed cells, graft-versus- leukemia effects following hematopoietic cell transplantation and antibody-dependent cell-mediated cytotoxicity (ADCC), in response to delivery of therapeutic antibodies. Targeting NK cells in situ, or delivery of ex vivo expanded NK cells are therapies underway that are safe, feasible and scalable because NK cells can be transplanted across allogeneic barriers without graft-versus-host complications. The function of NK cells varies within and between individuals as a result of variegated expression of germline-encoded ligands and a functional process called “education”, based on interactions with “self” human leukocyte antigens (HLA). Unlike T cells, NK cell killing is not HLA-restricted. The “educated” population of NK cells actually responds to cells that have lost HLA expression in a process called “missing self” reactivity. The “uneducated” population of NK cells functions to recognize stressed cells, but does not interact with “self” HLA molecules. Hence, NK cells may be ideal effectors against NSCLC because they can target both the HLA-sufficient and HLA-deficient phenotypes, but establishment of the functional roles of each of the educated and uneducated NK cell subsets will be important toward balancing their efficacy in NSCLC. In this operating grant, we will explore the conditions that enable NK-mediated recognition of NSCLC, with a focus on the educated and uneducated NK cell subsets. Using high parameter flow cytometry, we can identify additional features of both populations that may predict their function and become next-generation targets for immunotherapy. We will pursue the following specific aims: Aim 1: Determine how loss of HLA expression influences recognition of NSCLC by NK cells. Aim 2: Determine how recruitment of NK cell subsets influences the ultimate outcome of NSCLC. Significance: Our studies will demonstrate how NK cells may contribute to control of NSCLC, and highlight opportunities for intervention to maximize NK cells' contribution to cancer control. By leveraging the multifaceted mechanisms of target cell recognition of which different NK cell subsets are capable, it will become possible to more completely and durably control NSCLC.