Alternative titles; symbols
HGNC Approved Gene Symbol: CD274
Cytogenetic location: 9p24.1 Genomic coordinates (GRCh38) : 9:5,450,542-5,470,554 (from NCBI)
Engagement of CD28 (186760) by B7-1 (CD80; 112203) or B7-2 (CD86; 601020) in the presence of antigen promotes T-cell proliferation, cytokine production, differentiation of effector T cells, and the induction of BCLX (600039), a promoter of T-cell survival. Engagement of CTLA4 (123890) by B7-1 or B7-2, on the other hand, may inhibit proliferation and interleukin-2 (IL2; 147680) production. Antibody against the CD28-related molecule ICOS (604558) can stimulate T-cell growth and induce IL10 (124092) and IL4 (147780) production. By searching an EST database for B7-1 and B7-2 homologs, followed by RT-PCR of a placenta cDNA library, Dong et al. (1999) obtained a cDNA encoding B7H1 (B7 homolog-1). Sequence analysis predicted that the 290-amino acid type I transmembrane protein, which is 20% and 15% identical to B7-1 and B7-2, respectively, has immunoglobulin V-like and C-like domains and a 30-amino acid cytoplasmic tail. Northern blot analysis detected 4.1- and 7.2-kb B7H1 transcripts most abundantly in heart, skeletal muscle, placenta, and lung, with weak expression in thymus, spleen, kidney, and liver, and no expression in brain, colon, and small intestine. Fluorescence-activated cell sorting (FACS) analysis demonstrated B7H1 expression on a fraction of monocytes and, weakly, on T and B cells. Activation significantly increased expression on both T cells and monocytes, and, to a lesser extent, on B cells. Binding analysis demonstrated no interaction between B7H1 and ICOS, CTLA4, or CD28.
Freeman et al. (2000) also cloned B7H1, which they termed 'programmed cell death-1 (PDCD1, or PD1; 600244) ligand-1,' or PDL1. Mouse Pdl1 is 70% identical to the human protein. Flow cytometric and BIAcore analyses determined that PDL1 binds to PDCD1, but not to the structurally similar CTLA4, CD28, or ICOS proteins. RNA blot hybridization indicated that PDL1 was upregulated in monocytes by treatment with IFNG and in dendritic cells and keratinocytes by treatment with IFNG together with other activators. In dendritic cells, B7-1 and B7-2 were upregulated in parallel with PDL1. Expression of PDL1 was also upregulated in B cells activated by surface Ig cross-linking.
Dong et al. (1999) showed that stimulation of T cells in the presence of B7H1 enhanced proliferation and the preferential production of IL10 and gamma-interferon (IFNG; 147570), but not IL4, in an IL2-dependent manner.
Freeman et al. (2000) showed that activation of human T cells and murine Pdcd1 +/+ T cells in the presence of PDL1 led to a decrease in proliferation and cytokine secretion, possibly due to the presence of a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) on PDCD1.
Using immunohistochemical analysis, Dong et al. (2002) showed that B7H1 protein is expressed in most freshly isolated human cancers but not in most normal tissues. Flow cytometric analysis of tumor cell lines showed upregulation of B7H1 expression in response to, but rarely in the absence of, IFNG. Expression of B7H1, in the absence of other apoptosis-inducing ligands, in a melanoma cell line or a breast cancer-derived line, which are otherwise susceptible to cell-mediated cytolysis, induced T-cell death through a receptor other than PD1. Apoptosis could be partially inhibited by neutralization of FASL (TNFSF6; 134638) and IL10. Dong et al. (2002) proposed that cancer immunotherapy with preactivated T cells could be enhanced by blockade of B7H1.
Curiel et al. (2003) reported that myeloid dendritic cells (MDCs) obtained from draining lymph nodes of ovarian cancer patients, but not peripheral blood monocyte-derived MDCs from healthy individuals, expressed high levels of B7H1. Expression of B7H1 could be enhanced by VEGF (192240) or IL10, both of which were secreted by ovarian carcinoma cell lines, or by tumor-associated macrophages in the absence of anti-VEGF or anti-IL10. In the absence of anti-B7H1, normal allogeneic CD4 (186940)-positive or CD8 (see 186910)-positive T cells secreted IL10 in response to tumor MDCs. Blockade of B7H1 upregulated IL12 (see 161561) expression and enhanced antitumor immunity in NOD-SCID mice bearing ovarian tumors mediated by transfused normal T cells expressing IFNG. Curiel et al. (2003) concluded that upregulation of B7H1 on tumor MDCs downregulates T-cell immunity and that B7H1 blockade may represent an approach for cancer immunotherapy.
Using microarray analysis and flow cytometry, Barber et al. (2006) found that Pd1 was highly upregulated by functionally exhausted CD8 T cells from mice infected with a lymphocytic choriomeningitis virus (LCMV) strain causing chronic infection, but not by functional memory CD8 T cells from mice infected with an LCMV strain causing acute infection. FACS analysis showed that Pd1 expression was transiently upregulated on CD8 T cells in acutely infected mice. In contrast, Pd1 expression continued to rise and was sustained on virus-specific CD8 T cells in chronically infected mice. Pdl1 was highly expressed on virally infected cells. Treatment of chronically infected mice with a blocking antibody to Pdl1 enhanced CD8 T-cell function, leading to cytotoxic T-cell activity, production of Ifng and Tnf (191160), and substantially reduced virus levels with no overt signs of disease. The beneficial effects of Pdl1 blockade were also observed in mice depleted of helper CD4 T cells. Expression of Pd1 was not affected by anti-Pdl1 treatment, and CD8 T-cell function did not decline after cessation of treatment. Pdl1 -/- mice chronically infected with LCMV died due to immunopathologic damage, whereas Pdl1 -/- mice acutely infected with LCMV behaved like wildtype mice. Barber et al. (2006) concluded that antibody blockade of PDL1 may be an effective immunologic strategy for treatment of chronic viral infections, including human immunodeficiency virus, and virus-induced cancers, although the potential for autoimmunity and immunopathology must be carefully monitored.
In an analysis of 196 tumor specimens from patients with renal cell carcinoma (RCC; 144700), Thompson et al. (2004) found that high tumor expression of B7H1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death. The authors suggested that expression of B7H1 by tumor cells may impair host immunity and facilitate tumor progression. In a follow-up study, Krambeck et al. (2006) found that 94 (36%) of 259 renal cell carcinomas expressed both B7H1 and B7H4 (608162), another coregulatory molecule that inhibits T-cell activity. Expression of both B7H1 and B7H4 was associated with even greater tumor aggressiveness and increased risk of death than expression of either molecule alone.
In studies in human astrocytes engineered to contain alterations functionally equivalent to those seen in human malignant glioma, Parsa et al. (2007) demonstrated that expression of the PDCD1LG1 gene increased posttranscriptionally after loss of PTEN (601728) and activation of the PI3K (see 171834) pathway. Levels of B7H1 correlated with PTEN loss in glioblastoma specimens, and tumor-specific T cells lysed human glioma targets expressing wildtype PTEN more effectively than those expressing mutant PTEN. Parsa et al. (2007) concluded that immunoresistance in glioma is related to loss of the tumor suppressor PTEN and is mediated in part by B7H1.
Using paraffin-embedded specimens and immunohistochemistry, Hamanishi et al. (2007) showed that ovarian cancer patients with higher expression of PDL1 had a significantly poorer prognosis than those with lower expression of PDL1. High expression of PDL2 (PDCD1LG2; 605723) also tended towards a poor prognosis, but the finding was not statistically significant. A significant inverse correlation between PDL1 expression and intraepithelial CD8-positive T-lymphocyte count suggested that PDL1 on tumor cells may suppress antitumor CD8-positive T cells. Hamanishi et al. (2007) proposed that the PD1/PDL1 pathway may be a good target for restoring antitumor immunity in ovarian cancer.
Seo et al. (2007) reported that B7h1 expression was upregulated in mouse T cells, natural killer (NK) cells, and macrophages after infection with Listeria monocytogenes. B7h1 blockade increased mortality, inhibited Tnf and nitric oxide production by macrophages, and inhibited Ifng and granzyme B (GZMB; 123910) expression by NK cells. The blockade selectively inhibited Cd8-positive rather than Cd4-positive T-cell proliferation and cytokine production in response to L. monocytogenes antigens in both the effector and memory phases. Seo et al. (2007) proposed that B7H1 provides positive costimulatory signals for innate and adaptive immunity and for protection against intracellular bacterial infection.
Using flow cytometric analysis, Said et al. (2010) found that expression of PD1 (600244) was upregulated on CD16 (146740)-positive and CD16-negative monocytes, but not on dendritic cells, in viremic human immunodeficiency virus (HIV; see 609423)-positive patients, but not in highly active antiretroviral therapy (HAART)-treated HIV-positive patients. PD1 upregulation in monocytes was induced by microbial Toll-like receptor (TLR; see 603030) ligands and inflammatory cytokines. In HIV-positive patients, PD1 expression on CD16-positive or CD16-negative monocytes correlated with blood IL10 concentrations. Furthermore, triggering of PD1 by PDL1, but not by PDL2, induced monocyte IL10 production. PD1 triggering inhibited CD4-positive T-cell responses. IL10 stimulation increased STAT3 (102582) phosphorylation in CD4-positive T cells, and both CD4-positive and CD8-positive T lymphocytes showed increased PD1 expression in viremic HIV patients. Said et al. (2010) proposed that both IL10-IL10R (146933) and PD1-PDL1 interactions need to be blocked to restore the immune response during HIV infection.
Wang et al. (2012) found that expression of CD274 protein was upregulated in 88 (42.9%) of 205 gastric cancers (613659) compared with matched normal tissue. In contrast, there was no difference in CD274 mRNA expression between gastric cancer and normal tissues. Eighty of the 88 cancers with CD274 upregulation had a somatic G-to-C transition at cDNA position 1268 (1268G-C). The mutation occurred in the seed region of a putative binding site for microRNA-570 (MIR570; 614538) in the 3-prime UTR of CD274. Reporter gene assays and transfection studies confirmed that MIR570 downregulated CD274 expression in wildtype cells, but it did not downregulate CD274 expression in cancer cells with the 1268G-C mutation.
Using flow cytometry, Yang et al. (2013) examined expression of PD1 and PDL1 on cervical T cells and dendritic cells, respectively, from 40 women who were either positive or negative for high-risk human papillomavirus (HR-HPV) infection with different grades of cervical intraepithelial neoplasia (CIN). They found that PD1 and PDL1 expression was associated with HR-HPV positivity and that expression increased with increasing CIN grade. In contrast, expression of the CD80 and CD86 costimulatory markers decreased in HR-HPV-positive women in parallel with increasing CIN grade. Similarly, increased levels of the Th2 cytokine IL10 and decreased levels of the Th1 cytokines IFNG and IL12 (161560) in cervical exudates correlated with HR-HPV positivity and increased CIN grade. Yang et al. (2013) proposed that upregulation of the inhibitory PD1/PDL1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to progression of HR-HPV-related CIN.
Powles et al. (2014) examined the anti-PDL1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of urothelial bladder cancer (UBC; see 109800). MPDL3280A is a high-affinity engineered human anti-PDL1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PDL1 with PD1 (PDCD1; 600244) and B7.1 (CD80; 112203). Because PDL1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PDL1. Powles et al. (2014) found that treatment with MPDL3280A resulted in rapid responses in metastatic UBC, with many occurring at the time of the first response assessment (6 weeks). Nearly all responses were ongoing at the data cutoff. In a phase I expansion study, Powles et al. (2014) showed that tumors expressing PDL1-positive tumor-infiltrating immune cells had particularly high response rates. MPDL3280A has a favorable toxicity profile, including a lack of renal toxicity, which suggested that it might be better tolerated by patients with UBC than chemotherapy. Patients with UBC tend to be older and to have a higher incidence of renal impairment.
Kamphorst et al. (2017) demonstrated that the CD28 (186760)/B7 costimulatory pathway is essential for effective PD1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T-cell proliferation after PD1 blockade. B7 costimulation was also necessary for effective PD1 therapy in tumor-bearing mice. In addition, Kamphorst et al. (2017) found that CD8 T cells proliferating in blood after PD1 therapy of lung cancer patients were predominantly CD28-positive. Kamphorst et al. (2017) concluded that their data demonstrated a CD28 costimulation requirement for CD8 T-cell rescue and suggested an important role for the CD28/B7 pathway in PD1 therapy of cancer patients.
By titrating PD1 signaling in a biochemical reconstitution system, Hui et al. (2017) demonstrated that the coreceptor CD28 is strongly preferred over the T cell receptor (TCR; see 186880) as a target for dephosphorylation by PD1-recruited Shp2 (176876) phosphatase. Hui et al. (2017) also showed that CD28, but not the TCR, is preferentially dephosphorylated in response to PD1 activation by PDL1 in an intact cell system. Hui et al. (2017) concluded that PD1 suppresses T-cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T-cell function and responses to anti-PDL1/PD1 therapy.
Sugiura et al. (2019) demonstrated that CD80 (112203) interacts with PDL1 in cis on antigen-presenting cells to disrupt PDL1/PD1 (600244) binding. Subsequently, PDL1 cannot engage PD1 to inhibit T cell activation when antigen-presenting cells express substantial amounts of CD80. In knockin mice in which cis-PDL1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD1. Sugiura et al. (2019) concluded that CD80 on antigen-presenting cells limits the PD1 coinhibitory signal while promoting CD28-mediated costimulation, and highlighted critical components for induction of optimal immune responses.
Using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, Maier et al. (2020) identified a cluster of dendritic cells (DCs) that they named 'mature dendritic cells enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes and maturation genes. Maier et al. (2020) found that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumor antigens and further found that upregulation of PDL1, a key checkpoint molecule, in mregDCs is induced by the receptor tyrosine kinase AXL (109135), while upregulation of interleukin-12 (IL12; see 161560) depends strictly on interferon-gamma (IFNG; 147570) and is controlled negatively by IL4 (147780) signaling. Blocking IL4 enhances IL12 production by tumor antigen-bearing mregDC1s, expands the pool of tumor-infiltrating effector T cells, and reduces tumor burden. Maier et al. (2020) concluded that they uncovered a regulatory module associated with tumor-antigen uptake that reduces DC1 functionality in human and mouse cancers.
Using a proximity labeling approach to identify proteins localized to phagosomes containing model yeast and bacteria in mouse macrophages, followed by component analysis, Li et al. (2024) identified Pdl1 as a protein specifically enriched in phagosomes containing yeast. Human and mouse PDL1 bound directly to yeast upon processing in phagosomes, and the authors identified Rpl20b as the fungal protein ligand for PDL1. Further analysis showed that detection of Rpl20b by mouse macrophages cross-regulated production of cytokines, including Il10, induced by activation of other innate immune receptors.
Relationship to Tumor Immunity
PDL1, which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding PD1 (600244) and B7.1, both of which are negative regulators of T-lymphocyte activation. Binding of PDL1 to its receptors suppresses T-cell migration, proliferation, and secretion of cytotoxic mediators, and restricts tumor cell killing. The PDL1-PD1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Herbst et al. (2014) designed a study to evaluate the safety, activity, and biomarkers of PDL1 inhibition using the engineered humanized antibody MPDL3280A, and showed that across multiple cancer types, responses were observed in patients with tumors expressing high levels of PDL1, especially when PDL1 was expressed by tumor-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 gene expression, CTLA4 (123890) expression, and the absence of fractalkine (CX3CL1; 601880) in baseline tumor specimens. Herbst et al. (2014) concluded that MPDL3280A is most effective in patients in which preexisting immunity is suppressed by PDL1, and is reinvigorated on antibody treatment.
Tumeh et al. (2014) showed that preexisting CD8+ (186910) T cells distinctly located at the invasive tumor margin are associated with expression of the PD1/PDL1 immune inhibitory axis and may predict response to therapy. The authors analyzed samples from 46 patients with metastatic melanoma (155600) obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumors, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumor size. Pretreatment samples obtained from responding patients showed higher numbers of CD8-, PD1-, and PDL1-expressing cells at the invasive tumor margin and inside tumors, with close proximity between PD1 and PDL1, and a more clonal TCR repertoire. Using multivariate analysis, Tumeh et al. (2014) established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. The authors concluded that tumor regression after therapeutic PD1 blockade requires preexisting CD8+ T cells that are negatively regulated by PD1/PDL1-mediated adaptive immune resistance.
Xu et al. (2016) noted that chemoresistance limits the clinical application of effective chemotherapy for ovarian cancer (167000). Immune checkpoint blockade of the inhibitory immune receptors PD1 and CTLA4 and the immune ligand PDL1 is successful in treatment for several cancers. By in silico and RT-PCR analyses, Xu et al. (2016) found that expression of the microRNA (miRNA) MIR424 (300682) was inversely correlated with expression of PDL1, PD1, CD80, and CTLA4. High MIR424 level in tumors was positively correlated with progression-free survival in ovarian cancer patients. Functional analysis showed that MIR424 inhibited PDL1 and CD80 expression by directly binding their 3-prime UTRs. Restoration of MIR424 expression reversed chemoresistance, which was accompanied by blockage of the PDL1 immune checkpoint. Combining chemotherapy and immunotherapy was associated with proliferation of functional cytotoxic CD8-positive T cells and inhibition of myeloid-derived suppressor and regulatory T cells. Xu et al. (2016) proposed that there is a biologic and functional interaction between PDL1 and chemoresistance through the miRNA regulatory cascade.
Kataoka et al. (2016) demonstrated a unique genetic mechanism of immune escape caused by structural variations commonly disrupting the 3-prime region of the PDL1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these structural variants invariably lead to a marked elevation of aberrant PDL1 transcripts that are stabilized by truncation of the 3-prime untranslated region (UTR). Disruption of the Pdl1 3-prime UTR in mice enables immune evasion of EG7-OVA tumor cells with elevated Pdl1 expression in vivo, which is effectively inhibited by Pd1 (600244)-Pdl1 blockade, supporting the role of relevant structural variants in clonal selection through immune evasion. Kataoka et al. (2016) concluded that their findings not only unmasked a novel regulatory mechanism of PDL1 expression, but also suggested that PDL1 3-prime UTR disruption could serve as a genetic marker to identify cancers that actively evade antitumor immunity through PDL1 overexpression.
In mice, Dorand et al. (2016) demonstrated that Cdk5 (123831) allows medulloblastoma to evade immune elimination. Interferon-gamma (IFNG; 147570)-induced Pdl1 upregulation on medulloblastoma required Cdk5, and disruption of Cdk5 expression in a mouse model of medulloblastoma resulted in potent CD4+ T cell-mediated tumor rejection. Loss of Cdk5 resulted in persistent expression of the Pdl1 transcriptional repressors, the interferon regulatory factors Irf2 (147576) and Irf2bp2 (615332), which likely led to reduced Pdl1 expression on tumors.
Casey et al. (2016) demonstrated that MYC (190080) regulates the expression of 2 immune checkpoint proteins on the tumor cell surface: the innate immune regulator cluster of differentiation-47 (CD47; 601028) and the adaptive immune checkpoint PDL1. Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PDL1 mRNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pdl1 genes. MYC inactivation in mouse tumors downregulated CD47 and PDL1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PDL1, the immune response was suppressed, and tumors continued to grow. Thus, Casey et al. (2016) concluded that MYC appears to initiate and maintain tumorigenesis, in part through the modulation of immune regulatory molecules.
Using a haploid genetic screen, Mezzadra et al. (2017) identified CMTM6 (607882) as a regulator of PDL1 protein. Interference with CMTM6 expression resulted in impaired PDL1 protein expression in all human tumor cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, Mezzadra et al. (2017) demonstrated that this function is shared by its closest family member, CMTM4 (607887), but not by any of the other CMTM members tested. Notably, CMTM6 increases the PDL1 protein pool without affecting PDL1 (also known as CD274) transcription levels. Rather, Mezzadra et al. (2017) demonstrated that CMTM6 is present at the cell surface, associates with the PDL1 protein, reduces its ubiquitination, and increases PDL1 protein half-life. Consistent with its role in PDL1 protein regulation, CMTM6 enhances the ability of PDL1-expressing tumor cells to inhibit T cells. Mezzadra et al. (2017) concluded that their data revealed that PDL1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggested potential avenues to block this pathway.
Using a genomewide CRISPR-Cas9 screen, Burr et al. (2017) identified CMTM6 as a critical regulator of PDL1 in a broad range of cancer cells. CMTM6 is a ubiquitously expressed protein that binds PDL1 and maintains its cell surface expression. CMTM6 is not required for PDL1 maturation but colocalizes with PDL1 at the plasma membrane and in recycling endosomes, where it prevents PDL1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome, Burr et al. (2017) found that CMTM6 displays specificity for PDL1. Notably, CMTM6 depletion decreases PDL1 without compromising cell surface expression of MHC class I antigens. CMTM6 depletion, via the reduction of PDL1, significantly alleviates the suppression of tumor-specific T cell activity in vitro and in vivo. Burr et al. (2017) concluded that their findings provided insights into the biology of PDL1 regulation, identified a master regulator of this critical immune checkpoint, and highlighted a therapeutic target to overcome immune evasion by tumor cells.
Zhang et al. (2018) showed that PDL1 protein abundance is regulated by cyclin D (168461)-CDK4 (123829) and the cullin 3 (603136)-SPOP (602650) E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (603368) in vivo increases PDL1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1 (603619). Loss-of-function mutations in SPOP compromise ubiquitination-mediated PDL1 degradation, leading to increased PDL1 levels and reduced numbers of tumor-infiltrating lymphocytes in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD1 immunotherapy enhances tumor regression and markedly improves overall survival rates in mouse tumor models. Zhang et al. (2018) concluded that their study uncovered a novel molecular mechanism for regulating PDL1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD1-PDL1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
Chen et al. (2018) reported that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PDL1 on their surface. Stimulation with interferon-gamma (IFNG; 147570) increased the amount of PDL1 on these vesicles, which suppressed the function of CD8 T cells and facilitates tumor growth. In patients with metastatic melanoma, the level of circulating exosomal PDL1 positively correlated with that of IFNG, and varied during the course of anti-PD1 therapy. The magnitudes of the increase in circulating exosomal PDL1 during early stages of treatment, as an indicator of the adaptive response of the tumor cells to T cell reinvigoration, stratified clinical responders from nonresponders. Chen et al. (2018) concluded that their study unveiled a mechanism by which tumor cells systemically suppress the immune system, and provided a rationale for the application of exosomal PDL1 as a predictor for anti-PD1 therapy.
By PCR and somatic cell hybrid analysis, Freeman et al. (2000) mapped the PDL1 gene to chromosome 9. Scott (2000) mapped the B7H1 gene to chromosome 9 based on sequence similarity between the B7H1 sequence (GenBank AF177937) and the chromosome 9 clone RP11-574F11 (GenBank AL162253).
Matsumoto et al. (2004) investigated the roles of B7h1 and B7dc (Pdcd1lg2) using a murine allergic asthma model. They found constitutive expression of B7h1 on DCs, macrophages, B cells, and T cells in lungs of naive animals. Expression of B7h1 increased dramatically after allergen challenge. In contrast, B7dc had low constitutive expression, with some upregulation on DCs after allergen challenge. Treatment of mice with anti-B7dc at the time of allergen challenge, but not at the time of sensitization, significantly increased airway hyperreactivity and eosinophilia in association with increased production of Il5 (147850) and Il13 (147683) and decreased production of Ifng. These changes were diminished in mice pretreated with anti-Ifng, but not with anti-B7h1 or anti-Pd1. Matsumoto et al. (2004) concluded that B7DC is involved in the regulation of the asthmatic response in an IFNG-dependent, PD1-independent manner.
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