Cells of the innate immunity play an important role in tumor immunotherapy. Thus,
NK cells can control tumor growth and metastatic spread. Thanks to their strong cytolytic
activity against tumors, different approaches have been developed for exploiting/harnessing
their function in patients with leukemia or solid tumors. Pioneering trials were based
on the adoptive transfer of autologous NK cell-enriched cell populations that were
expanded in vitro and co-infused with IL-2. Although relevant results were obtained
in patients with advanced melanoma, the effect was mostly limited to certain metastatic
localizations, particularly to the lung. In addition, the severe IL-2-related toxicity
and the preferential IL-2-induced expansion of Treg limited this type of approach.
This limitation may be overcome by the use of IL-15, particularly of modified IL-15
molecules to improve its half-life and optimize the biological effects. Other approaches
to harness NK cell function include stimulation via TLR, the use of bi- and tri-specific
NK cell engagers (BiKE and TriKE) linking activating NK receptors (e.g. CD16) to tumor-associated
antigens and even incorporating an IL-15 moiety (TriKE). As recently shown, in tumor
patients, NK cells may also express inhibitory checkpoints, primarily PD-1. Accordingly,
the therapeutic use of checkpoint inhibitors may unleash NK cells against PD-L1+ tumors.
This effect may be predominant and crucial in tumors that have lost HLA cl-I expression,
thus resulting "invisible" to T lymphocytes. Additional approaches in which NK cells
may represent an important tool for cancer therapy, are to exploit the unique properties
of the "adaptive" NK cells. These CD57+ NKG2C+ cells, despite their mature stage and
a potent cytolytic activity, maintain a strong proliferating capacity. This property
revealed to be crucial in hematopoietic stem cell transplantation (HSCT), particularly
in the haplo-HSCT setting, to cure high-risk leukemias. T depleted haplo-HSCT (e.g.
from one of the parents) allowed to save the life of thousands of patients lacking
a HLA-compatible donor. In this setting, NK cells have been shown to play an essential
role against leukemia cells and infections. Another major advance is represented by
chimeric antigen receptor (CAR)-engineered NK cells. CAR-NK, different from CAR-T
cells, may be obtained from allogeneic donors since they do not cause GvHD. Accordingly,
they may represent "off-the-shelf" products to promptly treat tumor patients, with
affordable costs. Different from NK cells, helper ILC (ILC1, ILC2 and ILC3), the innate
counterpart of T helper cell subsets, remain rather ambiguous with respect to their
anti-tumor activity. A possible exception is represented by a subset of ILC3: their
frequency in peri-tumoral tissues in patients with NSCLC directly correlates with
a better prognosis, possibly reflecting their ability to contribute to the organization
of tertiary lymphoid structures, an important site of T cell-mediated anti-tumor responses.
It is conceivable that innate immunity may significantly contribute to the major advances
that immunotherapy has ensured and will continue to ensure to the cure of cancer.