21 This balance of positive and negative signaling helps NK cells distinguish between transformed cells such as tumors and MHC class-I non-expressing cells like erythrocytes. which can be recognized by activating NK cell receptors such as NKG2D. Moreover, many transformed cell populations increase the expression of stress-induced molecules, including MHC class-I polypeptide-related sequence A and B (MICA and MICB). 19, 20 Thus, cells that do not express self-MHC class-I are targets for NK cell killing, which is directly relevant to the control of tumors that have downregulated MHC expression. 18 NK cells express killer inhibitory receptors (KIRs) such as CD158b, CD158e1, and killer cell lectin-like receptor subfamily C, member 1 (CD94/NKG2A) that engage the self-MHC class-I and results in a negative activation signal. 14- 17 NK cell function is regulated by a balance in activating and inhibitory receptor signaling. 12 NK cells, which are naturally cytotoxic innate lymphoid cells with intrinsic anti-tumor properties, 13 are emerging as key targets for cancer immunotherapy. 5- 11 The human innate immune system has a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment. The primary cellular mediators of immunotherapies are T cells, B cells, natural killer (NK) cells, and macrophages. 1, 2 However, there are groups of cancer patients that do not benefit from current immunotherapies, 3, 4 leading to the challenge of testing and validating new therapies or combination of therapies that increase response rates and prolong survival in a wider range of individuals. Immunotherapy has revolutionized the treatment of human malignancies and has proven to be efficacious against a variety of cancers with improved long-term survival rates. t-distributed stochastic neighbor embedding.Together, these data demonstrate that HSC-engrafted NSG-Tg(Hu-IL15) mice support enhanced development of functional human NK cells, which limit the growth of PDX tumors. Moreover, the growth kinetics of a patient-derived xenograft (PDX) melanoma were significantly delayed in HSC-engrafted NSG-Tg(Hu-IL15) mice as compared to HSC-engrafted NSG mice demonstrating that human NK cells have a key role in limiting the tumor growth. Hematopoietic stem cell (HSC)-engrafted NSG-Tg(Hu-IL15) mice also supported the development of human CD3+ T cells, CD20+ B cells, and CD33+ myeloid cells. Following hematopoietic stem cell engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of functional human CD56+ NK cells are detectable in blood and spleen, as compared to NSG mice. To enhance NK cell development, we have developed NSG mice that constitutively expresses human Interleukin 15 (IL15), NSG-Tg(Hu-IL15).

However, human NK cell development and survival in humanized NOD- scid-IL2rg null (NSG) mice are severely limited. Humanized mice are a powerful alternative to syngeneic mouse tumor models for the study of human immuno-oncology and have proven effective tools to test immunotherapies targeting T cells. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function in tumorigenesis.

Natural killer (NK) cells are innate lymphoid cells that have opposing roles in the tumor microenvironment, including NK cell subsets that mediate tumor cell cytotoxicity and subsets with regulatory function that contribute to the tumor immune suppressive environment. Human innate immunity plays a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment.

Nod scid mice