Adoptive NK T-Cells in Cancer Therapy

Adoptive NK T-Cells in Cancer Therapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

  Adoptive transfer of NK cells

Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer

Jeffrey S. Miller, Yvette Soignier, Angela Panoskaltsis-Mortari, …,Ian J. Okazaki, and Philip B. McGlave

We previously demonstrated that autologous natural killer (NK)–cell…

Cancer’s ability to evade and manipulate the immune system has proven to be a major obstacle for biomedical researchers struggling to develop treatment strategies.  As our understanding of tumor physiology has increased, the magnitude and variety of ways in which cancers can influence immune responses has become apparent.  One common primary target for inhibition by cancers, and for study by researchers, is the adaptive T cell response.  The microenvironment generated in tumors is able to suppress T cell responses or bias them toward anergy or tolerance at multiple points (Reviewed in Rabinovich et al., 2007).  Some characteristics of tumors have been shown to favor reduced immune cell recruitment to tumor sites and generation of tolerance.  For example, overactive Stat3 signaling observed in many malignancies leads to the production of vascular endothelial growth factor (VEGF) and IL-10 by tumor cells.  VEGF and IL-10 both produce tolerogenic phenotypes in dendritic cells (DCs) by impairing maturation, NF-κB translocation and, subsequently, upregulation of antigen presentation and co-stimulatory molecules, such as CD80/86 (Niu et al., 2002, Rabinovich et al., 2007, Steinbrink et al., 1997).  This inhibition of DC maturation leads to decreased migration to lymph nodes, reduced capacity to activate T cells, and a tendency to induce anergy to tumor-derived antigens via presentation in the absence of co-stimulation.  As is often noted when describing immunotherapeutic treatment of cancer, some patients benefit more than others.  One suspected culprit of this discrepancy is differential trafficking of effector cells (especially adoptively transferred T cells) to the tumor site related to the expression of chemokines.  The underlying cause of this phenomenon is not well characterized, but it has been observed in many systems (reviewed by Abastado, 2012).  The immunosuppression associated with tumors has also been correlated to the function of regulatory CD4+ T cells (Tregs).  While the precise mechanism of their induction in this system is still unclear, high numbers of Tregs in malignancies is known to predict poor patient prognoses and ablation of Tregs using anti-CD25 monoclonal antibodies significantly increased T cell-mediated tumor clearance (Curiel et al., 2004, Shimizu et al., 1999).   Several tumor tissues have been shown to express B7-H1, a member of the B7 co-stimulatory molecule family.  B7-H1 binds programmed death receptor 1 (PD-1) on T cells and promotes apoptosis, resulting in increased resistance of B7-H1 expressing tumors to T cell-mediated clearance (Dong et al., 2002).