NK cells are the primary orchestrator of immune responses to solid tumors

NK cells, in contrast to CD8+ T cells, do not require activation by a specific T-cell receptor tumor cell antigen interaction. Instead, the individual's collected population of NK cells, with an extensive diversity of expression of different activating and inhibiting receptors all coded in the germline, are "licensed" by prior interaction with a diversity of normal cells, to recognize and destroy abnormal cells using non-antigenic cues such as loss of surface HLA expression. NK cells occur in two general ontogenies, CD56 "dim" and CD56 "bright", which appear to have different functions. CD56 dim cells cause direct tumor cell killing mediated via cell-cell contact and granzyme; CD56 bright cells, upon activation, release chemokines and cytokines to attract the infiltration of dendritic and CD8+ T cells into the tumor microenvironment, thus enabling dendritic cells to directly sample potential neoantigens in the wake of NK-dim mediated destruction. The most successful outcome of NK activation and tumor killing is both loss of tumor mass due to NK activity, along with initiation of an anti-tumor adaptive response.

Activated T cells can drive cell death after engagement of their highly specific T cell receptor alone. For therapeutic approaches like CAR-T cells, this mean that even normal cells expressing the target antigen may be killed, and thus the therapeutic index of a CAR-T therapy is highly dependent on lack of expression of the target on normal tissue. Because NK cells integrate information from many different receptors, they are far less likely to kill normal cells expressing a target antigen, and thus the therapeutic index of NK based therapies (either CAR NK or NK plus engager) is far greater than for CAR T cells.