ABSTRACT
Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Inflammation/immunology , Killer Cells, Natural/immunology , Leishmania donovani/physiology , Leishmaniasis, Visceral/immunology , Malaria/immunology , Membrane Proteins/metabolism , Plasmodium/physiology , Animals , Cells, Cultured , Cytotoxicity, Immunologic , Disease Models, Animal , Exocytosis , Humans , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Secretory Vesicles/metabolismABSTRACT
Multiple non-redundant immunosuppressive pathways co-exist in the tumor microenvironment and their co-targeting can increase clinical responses. Indeed, concurrent blockade of CTLA-4 and PD-1 in patients with advanced melanoma increased clinical responses over monotherapy alone although the frequency and severity of immune related adverse events (irAEs) also increased. Nevertheless, a substantial number of patients still display an innate resistance phenotype and are unresponsive to current approved immunotherapies even when utilized in combination. In this study, we generated Pdcd1-/-CD96-/- and Tigit-/-CD96-/- mice to investigate how loss of CD96 in combination with PD-1 or TIGIT impacts on immune homeostasis and hence the potential of inducing immune related toxicities following co-targeting of these pairs of receptors. The ability of Pdcd1-/-CD96-/- and Tigit-/-CD96-/- mice to suppress primary tumor growth was also assessed using the MC38 colon carcinoma and SM1WT1 BRAF-mutated melanoma tumor models. Both Pdcd1-/-CD96-/- or Tigit-/-CD96-/- mice displayed no overt perturbations in immune homeostasis over what was previously reported with Pdcd1-/- or Tigit-/- mice even when aged for 22 months. Interestingly, increased suppression of subcutaneous tumor growth and complete responses was seen in Pdcd1-/-CD96-/- mice compared to Pdcd1-/- or CD96-/- mice depending upon the tumor model. In contrast, in these models, growth suppression in Tigit-/-CD96-/- were similar to Tigit-/- or CD96-/- . This enhanced anti-tumor efficacy of Pdcd1-/-CD96-/- appeared to be due to favorable changes in the ratio of CD8+ T cells to T regulatory cells or CD11b+GR-1hi myeloid cells in the tumor microenvironment. Co-targeting CD96 and PD-1 may increase anti-tumor immunity over targeting PD-1 alone and potentially not induce serious immune-related toxicities and thus appears a promising strategy for clinical development.
