No abstract

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.

Recent clinical trials using immunotherapy demonstrate its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies such as anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-Programmed cell death protein 1/anti-Programmed death-ligand 1 (anti-PD-1/anti-PD-L1)1 have demonstrated durable clinical responses in various cancers. Although these new immunotherapies have significant impact on cancer treatment, multiple mechanisms of immune resistance exist in tumors. Among the key mechanisms, myeloid cells play a major role in limiting effective tumor immunity. 2–4 Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. 5,6 These observations suggest a need for a precision medicine approach where the design of the immunotherapeutic combinations are tailored based on tumor immune landscape to overcome such resistance mechanisms. Herein we employ a preclinical model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumors. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3K–γ, with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumor immune microenvironment and promote cytotoxic T cell-mediated tumor regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3K-γ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumors.

MaterialMelanocyte differentiation Ags, including tyrosinase-related protein (TRP) 1, are relevant to both autoimmune skin depigmentation (vitiligo) and tumor immunity, because they are expressed by both benign melanocytes and many malignant melanomas. Melanoma patients generate CD4 + T cells that specifically recognize these proteins. TRP1 contains internal disulfide bonds and is presented by MHC class II molecules. g-IFN-inducible lysosomal thiol reductase (GILT) facilitates the generation of class II-binding peptides by the endocytic reduction of protein disulfide bonds. We show in this study that GILT is required for efficient MHC class II-restricted processing of a TRP1 epitope in vitro and accelerates the onset of vitiligo in TRP1-specific TCR transgenic mice. The presence of GILT confers a small increase in the percentage of autoreactive T cells with an effector memory phenotype that may contribute to earlier disease onset. The onset of vitiligo is associated with a greater increase in the percentage of autoreactive T cells with an effector memory phenotype. Given that many self and tumor Ags have disulfide bonds and are presented on MHC class II, GILT is likely to be important in the pathogenesis of other CD4 + T cell-mediated autoimmune diseases and for the development of effective cancer immunotherapy. The Journal of Immunology, 2010, 185: 2828-2835.G amma-IFN inducible lysosomal thiol reductase (GILT) is expressed in APCs, where it localizes to MHC class II-loading compartments (1-5). Its expression can be induced by IFN-g in other cell types, including melanomas (1, 4, 6). GILT is synthesized as a precursor and targeted via the mannose-6 phosphate receptor to the endocytic pathway where N-and C-terminal propeptides are removed to generate the mature form (7) found in multivesicular late endosomes and multilamellar lysosomes (1, 5). A minor amount of enzymatically active precursor is secreted as a disulfide-linked dimer (7). A thioredoxin-like CXXC motif constitutes the active site (1) of the enzyme, which facilitates the generation of MHC class II-restricted epitopes from disulfide bondcontaining Ags, such as hen egg lysozyme (HEL), HIV-1 envelope protein, and a cysteinylated peptide from Ig k (5,6,8,9). Despite the fact that not all HEL epitopes are dependent on GILT, the CD4 + T cell recall response to HEL in GILT 2/2 mice is about one-tenth of that seen in wild-type mice (5). Similar reductions in recall responses are seen upon immunization with other Ags containing disulfide bonds (5). Melanocyte differentiation Ags, such as tyrosinase, tyrosinaserelated protein (TRP) 1 (also called gp75), and TRP2, are melanosomal integral membrane proteins involved in melanin pigment synthesis. These Ags contain a dileucine-based sorting signal that targets them to the endosomal system where they can be processed for MHC class II-restricted presentation (10). Tyrosinase and TRPs have 16-19 cysteine residues (11), and internal disulfide bonds are present based on biochemical analyses and homology with plant cate...