A Natural Impact: NK Cells at the Intersection of Cancer and HIV Disease

Abstract

Despite efficient suppression of plasma viremia in people living with HIV (PLWH) on cART, evidence of HIV-induced immunosuppression remains, and normally benign and opportunistic pathogens become major sources of co-morbidities, including virus-induced cancers. In fact, cancer remains a primary cause of death even in virally suppressed PLWH. Natural killer (NK) cells provide rapid early responses to HIV infection, contribute substantially to disease modulation and vaccine protection, and are also major therapeutic targets for cancer immunotherapy. However, much like other lymphocyte populations, recent burgeoning evidence suggests that in chronic conditions like HIV, NK cells can become functionally exhausted with impaired cytotoxic function, altered cytokine production and impaired antibody-dependent cell-mediated cytotoxicity. Recent work suggests functional anergy is likely due to low-level ongoing virus replication, increased inflammatory cytokines, or increased presence of MHC^low target cells. Indeed, HIV-induced loss of NK cell-mediated control of lytic EBV infection has been specifically shown to cause lymphoma and also increases replication of CMV. In this review, we will discuss current understanding of NK cell modulation of HIV disease, reciprocal exhaustion of NK cells, and how this may impact increased cancer incidences and prospects for NK cell-targeted immunotherapies. Finally, we will review the most recent evidence supporting adaptive functions of NK cells and highlight the potential of adaptive NK cells for cancer immunotherapy.

Keywords: HIV; cancer; immunotherapy; innate immunity; natural killer.

Figure 1

Rescuing and harnessing NK cell potency in PLWH developing cancers. Left: HIV-infected and cancer cells share common NK cell escape mechanisms. 1. Over-engagement of inhibitory receptors (i.e., NKG2A, inhibitory KIRs, PD-1…) blocks killing abilities of NK cells. 2. Down-modulation (blocking expression of ligand or shedding of ligand) or over-exposure (constant expression of ligands or release of soluble ligands) induce down-expression of activating receptors (NKG2D, NCRs, DNAM-1…) on NK cells. Right: Novel immunotherapies are being develop to harness NK cell potency and target HIV-infected and cancer cells. 1. Monoclonal antibodies (mAb) release engagement of inhibitory receptors, unleash NK cell cytotoxicity and engage Fc receptors (CD16) to induce ADCC. Several clinical trials are in progress. 2. Engineered proteins, Bi-specific or Tri-specific Killer engagers (BiKEs or TriKEs) and Chimeric Antigen Receptors (CARs), act as a link between NK cells and target cells to induce cytotoxicity. BiKEs or TriKEs induce ADCC by engaging CD16 receptors and bind to antigen on target cells. 3. Adaptive features of NK cells, defined by a higher expression of CD57, NKG2C, and/or absence of FcR-γ, could be harnessed to elicit specific killing of target cells.