Farnesyltransferase inhibitor FTI‐277 inhibits PD‐L1 expression on septic spleen lymphocytes and promotes spleen lymphocyte activation

Farnesyltransferase inhibitors have been tested in clinical trials for the treatment of tumours. In sepsis, the binding of programmed death 1 (PD‐1) to programmed death ligand 1 (PD‐L1) promotes lymphocyte apoptosis and decreases cytokine expression, thus affecting survival rates. The PD‐1/PD‐L1 pathway plays an important role in chronic viral infection, bacterial infection and sepsis. However, the precise immunosuppressive and anti‐inflammatory functions of this pathway remain poorly understood. In our previous study, the induction of sepsis by caecal ligation and puncture (CLP) resulted in increased farnesyltransferase activity and farnesylated protein levels in the spleen relative to sham treatment. However, the effect of inhibition of farnesyltransferase activity on overall survival rates in patients with sepsis and the specific signalling pathway involved remain to be investigated. In this study, mice with CLP‐induced sepsis were treated with farnesyltransferase inhibitor (FTI‐277), and PD‐L1 expression on septic spleen lymphocytes was examined. Flow cytometric analysis revealed that PD‐L1 is expressed constitutively on lymphocytes and that PD‐L1 protein expression was up‐regulated strongly following CLP. FTI‐277 down‐regulated PD‐L1 mRNA and protein expression on septic spleen lymphocytes in a dose‐dependent manner. This effect was associated closely with nuclear factor kappa B (NF‐κB). In addition, the significant damping effect of FTI‐277 on the PD‐L1 signal promoted interferon (IFN)‐γ secretion, interleukin (IL)‐2 production and splenocyte proliferation in response to anti‐CD3⁺CD28⁺ antibodies in mice. Furthermore, FTI‐277 reduced spleen lymphocyte apoptosis in septic mice. Therefore, FTI‐277 regulates spleen lymphocyte activity via the PD‐L1 signalling pathway, with significant anti‐inflammatory effects attributable to suppression of the NF‐κB pathway. Farnesyltransferase represents a valuable therapeutic target for the treatment of sepsis.     

Programmed death (PD)‐1 molecule and its ligand PD‐L1 distribution among memory CD4 and CD8 T cell subsets in human immunodeficiency virus‐1‐infected individuals

Human immunodeficiency virus (HIV)‐1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti‐HIV‐1‐specific responses: programmed death (PD)‐1 molecule and its ligand PD‐L1 are negative regulators of T cell activity and their expression is increased during HIV‐1 infection. This study examines correlations between T cell maturation, expression of PD‐1 and PD‐L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV‐1⁺ and 17 uninfected individuals were phenotyped for PD‐1 and PD‐L1 expression on CD4⁺ and CD8⁺ T cell subsets. The effect of PD‐1 and PD‐L1 blockade on proliferation and interferon (IFN)‐γ production was tested on eight HIV‐1⁺ patients. Naive (CCR7⁺CD45RA⁺) CD8⁺ T cells were reduced in HIV‐1 aviraemic (P = 0·0065) and viraemic patients (P = 0·0130); CD8 T effector memory subsets [CCR7^‐CD45RA^–(T_EM)] were increased in HIV‐1⁺ aviraemic (P = 0·0122) and viraemic (P = 0·0023) individuals versus controls. PD‐1 expression was increased in CD4 naive (P = 0·0496), central memory [CCR7⁺CD45RA^– (T_CM); P = 0·0116], T_EM (P = 0·0037) and CD8 naive T cells (P = 0·0133) of aviraemic HIV‐1⁺versus controls. PD‐L1 was increased in CD4 T_EMRA (CCR7^‐CD45RA⁺, P = 0·0119), CD8 T_EM (P = 0·0494) and CD8 T_EMRA (P = 0·0282) of aviraemic HIV‐1⁺versus controls. PD‐1 blockade increased HIV‐1‐specific proliferative responses in one of eight patients, whereas PD‐L1 blockade restored responses in four of eight patients, but did not increase IFN‐γ‐production. Alteration of T cell subsets, accompanied by increased PD‐1 and PD‐L1 expression in HIV‐1 infection contributes to anergy and impaired anti‐HIV‐1‐specific responses which are not rescued when PD‐1 is blocked, in contrast to when PD‐L1 is blocked, due possibly to an ability to bind to receptors other than PD‐1.     

Anti‐CD3 treatment up‐regulates programmed cell death protein‐1 expression on activated effector T cells and severely impairs their inflammatory capacity

T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T‐cell receptor complex provides one therapeutic approach. Anti‐CD3 treatment can reverse overt disease in spontaneously diabetic non‐obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti‐CD3 treatment on green fluorescent protein (GFP)⁺ islet‐specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time‐points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti‐CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon‐γ. Programmed cell death protein 1 (PD‐1) expression was up‐regulated on the effector cells from anti‐CD3‐treated mice, and diabetes induced through anti‐PD‐L1 antibody could only be reversed with anti‐CD3 antibody if the anti‐CD3 treatment lasted beyond the point when the anti‐PD‐L1 antibody was washed out of the system. This suggests that PD‐1/PD‐L1 interaction plays an important role in the anti‐CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti‐CD3 therapy can reverse diabetogenesis.     

Severe functional impairment and elevated PD‐1 expression in CD1d‐restricted NKT cells retained during chronic HIV‐1 infection

Invariant CD1d‐restricted NKT cells play important roles in regulating both innate and adaptive immunity. They are targeted by HIV‐1 infection and severely reduced in number or even lost in many infected subjects. Here, we have investigated the characteristics of NKT cells retained by some patients despite chronic HIV‐1 infection. NKT cells preserved under these circumstances displayed an impaired ability to proliferate and produce IFN‐γ in response to CD1d‐restricted lipid antigen as compared with cells from uninfected control subjects. HIV‐1 infection was associated with an elevated expression of the inhibitory programmed death‐1 (PD‐1) receptor (CD279) on the CD4^? subset of NKT cells. However, blocking experiments indicated that the functional defects in NKT cells were largely PD‐1‐independent. Furthermore, the elevated PD‐1 expression and the functional defects were not restored by anti‐retroviral treatment, and the NKT cell numbers in blood did not recover significantly in response to treatment. The functional phenotype of NKT cells in these patients suggests an irreversible immune exhaustion due to chronic activation in vivo. The data demonstrate a severe functional impairment in the remaining NKT‐cell compartment in HIV‐1‐infected patients, which limits the prospects to mobilize these cells in immunotherapy approaches in patients.     

PD‐L1 expression on tumor or stromal cells of nodal cytotoxic T‐cell lymphoma: A clinicopathological study of 50 cases

Inhibitors of programmed cell‐death 1 (PD‐1) and programmed cell‐death ligand 1 (PD‐L1) have revolutionized cancer therapy. Nodal cytotoxic T‐cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non‐CTLs. Here we investigated PD‐L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD‐L1 (nPD‐L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαβ type, three were TCRγδ type and three were TCR‐silent type. Six of the seven cases exhibited a lethal clinical course despite multi‐agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD‐L1⁺ cases, two of three examined had structural variations of PD‐L1 disrupting 3′‐UTR region. Notably, all of the TCRγδ‐type nodal CTL cases showed nPD‐L1 or miPD‐L1 positivity (3 and 10 cases, respectively). TCRγδ‐type cases comprised 42% of nPD‐L1⁺ cases (P = 0.043 vs. PD‐L1^?), and 35% of miPD‐L1⁺ cases (P = 0.037 vs. PD‐L1^?). The results indicate that PD‐L1⁺ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti‐PD‐1/PD‐L1 therapies.     

PD‐1 regulates extrathymic regulatory T‐cell differentiation

Treg cells and the programed death‐1/programed death ligand‐1 (PD‐1/PD‐L1) pathway are both critical for maintaining peripheral tolerance to self‐Ags. A significant subset of Treg cells constitutively expresses PD‐1, which prompted an investigation into the role of PD‐1/PD‐L1 interactions in Treg‐cell development, function, and induction in vivo. The phenotype and abundance of Treg cells was not significantly altered in PD‐1‐deficient mice. The thymic development of polyclonal and monospecific Treg cells was not negatively impacted by PD‐1 deficiency. The suppressive function of PD‐1^?/? Treg cells was similar to their PD‐1^+/+ counterparts both in vitro and in vivo. However, in three different in vivo experimental settings, PD‐1^?/? conventional CD4⁺ T cells demonstrated a strikingly diminished tendency toward differentiation into peripherally induced Treg (pTreg) cells. Our results demonstrate that PD‐1 is dispensable for thymic Treg‐cell development and suppressive function, but is critical for the extrathymic differentiation of pTreg cells in vivo. These data suggest that Ab blockade of the PD‐1/PD‐L1 pathway may augment T‐cell responses by acting directly on conventional T cells, and also by suppressing the differentiation of pTreg cells.     

Differential control of CD4+ T‐cell subsets by the PD‐1/PD‐L1 axis in a mouse model of allergic asthma

Studies examining the role of PD‐1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD‐1/PD‐L1 has distinct influences on different CD4⁺ T‐cell subsets. PD‐1/PD‐L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2‐type immune response, but by allowing the development of a concomitant Th17‐type immune response. Supporting differential CD4⁺ T‐cell responsiveness to PD‐1‐mediated inhibition, naïve PD‐1^?/? mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD‐1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD‐1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4⁺ T‐cell subsets respond differentially to PD‐1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD‐1 family members. As the PD‐1/PD‐L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD‐1/PD‐L1 regulatory axis in some individuals.     

Exposure to anti‐PD‐1 causes functional differences in tumor‐infiltrating lymphocytes in rare solid tumors

The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD‐1) to boost anti‐tumor immunity has positioned this approach to become the standard‐of‐care for some solid tumor malignancies. However, little is known as to how blockade of PD‐1 may alter the function or phenotype of tumor‐infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti‐PD‐1 (15–21 days post‐dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8⁺ and CD4⁺ TIL populations. An enriched CTLA‐4 expression in the CD4⁺ TIL population was observed in TIL expanded from the on‐treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on‐treatment. The CD8⁺ TIL population demonstrated a diminished cytokine secretion profile post‐pembrolizumab. Overall, our study assesses the ramifications of one dose of anti‐PD‐1 on TIL in rare solid tumor types.     

PD‐1/PD‐L1 inhibitors in haematological malignancies: update 2017

The introduction of PD‐1/PD‐L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice‐changing activity in various types of solid tumours. Among haematological malignancies, PD‐1/PD‐L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over‐expression of PD‐1 ligands (PD‐L1, PD‐L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication. Although the results in other lymphoid malignancies have not been so striking, blockade of the PD‐1/PD‐L1 axis has led to meaningful responses in other lymphoma types such as diffuse large B‐cell lymphoma, follicular lymphoma or several T‐cell lymphomas. Monotherapy with PD‐1/PD‐L1 inhibitors in chronic lymphocytic leukaemia and multiple myeloma has been unsatisfactory, suggesting that a combinational approach with other synergistic drugs is needed. In the case of multiple myeloma, immunomodulatory agents together with corticosteroids represent the most promising combinations. Among myeloid malignancies, the anti‐PD‐1 monoclonal antibodies are examined dominantly in acute myeloid leukaemia and myelodysplastic syndromes in combination with potentially synergistic hypomethylating drugs such as 5‐azacitidine, resulting in promising outcomes that warrant further investigation. We have described all available clinical results of PD‐1/PD‐L1 inhibitors in haematological malignancies and discussed related toxicities, as well as highlighted crucial preclinical studies in this review.     

Programmed death‐1+ T cells inhibit effector T cells at the pathological site of miliary tuberculosis

Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death‐1 (PD‐1) is a key immune check‐point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD‐1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD‐1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD‐1–PD‐ligand 1 (PD‐L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD‐1 and its ligands (PD‐L1–PD‐L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage‐derived CD3 T cells in MTB expressed PD‐1 (54·2 ± 27·4%, P ≥ 0·0009) with significantly higher PD‐1 ligand‐positive T cells (PD‐L1: 19·8 ± 11·8%; P ≥ 0·019, PD‐L2: 12·6 ± 6·2%; P ≥ 0·023), CD19⁺ B cells (PD‐L1: 14·4 ± 10·4%; P ≥ 0·042, PD‐L2: 2·6 ± 1·43%; not significant) and CD14⁺ monocytes (PD‐L1: 40·2 ± 20·1%; P ≥ 0·047, PD‐L2: 22·4 ± 15·6%; P ≥ 0·032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD‐1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)?2 and elevated apoptosis. Locally accumulated T cells were predominantly PD‐1⁺–PD‐L1⁺, and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD‐1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby favouring disease dissemination.     

Mesenteric lymph node CD11b− CD103+ PD‐L1High dendritic cells highly induce regulatory T cells

Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3⁺ regulatory T cells to regulate immune responses to beneficial or non‐harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103⁺ DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD‐L1) ‐deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c⁺ cells. Four distinct subsets expressing CD103 and/or PD‐L1 were identified, namely CD11b⁺ CD103⁺ PD‐L1^High, CD11b⁻ CD103⁺ PD‐L1^High, CD11b⁻ CD103⁺ PD‐L1^Low and CD11b⁺ CD103⁻ PD‐L1^Int. Among them, the CD11b⁻ CD103⁺ PD‐L1^High DC subset highly induced Foxp3⁺ T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor‐β (TGF‐β) activation, respectively. Exogenous TGF‐β supplementation equalized the level of Foxp3⁺ T‐cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF‐β is determinant for the high Foxp3⁺ T‐cell induction by CD11b⁻ CD103⁺ PD‐L1^High DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b⁻ CD103⁺ PD‐L1^High DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF‐β activation.     

Recent Insight into the Role of the PD‐1/PD‐L1 Pathway in Feto‐Maternal Tolerance and Pregnancy

Pregnancy presents a great challenge to the maternal immune system. Given that maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to serve a central function in altering the maternal immune responses. Regulatory T cells (Tregs) and the PD‐1/PD‐L1 pathway are both critical in controlling the immune responses. Recent studies have proved the critical function of the PD‐1/PD‐L1 pathway in regulating the T‐cell homeostasis and the peripheral tolerance through promoting the development and function of Tregs, and inhibiting the activation of effector T cells. The function of the PD‐1/PD‐L1 pathway in feto‐maternal interface and pregnancy has been investigated in human and animal models of pregnancy. In this review, we provide recent insight into the role of the PD‐1/PD‐L1 pathway in regulating T‐cell homeostasis, maternal tolerance, and pregnancy‐related complications as well as its possible applicability in clinical immunotherapy.     

New Dancing Couple: PD‐L1 and MicroRNA

Lung cancer (LC) is the most common cause of cancer death in the world. A great challenge in treating NSCLC is the discovery of advanced, molecular tools to diagnose the disease in early stages as well as the development of immunotherapy. MicroRNAs are regulatory molecules (~20 nt in length) with the ability to regulate the expression of genes. The recently described PD‐1 and PD‐L1 molecules have great importance for potential use in immunotherapy of many cancers. These molecules are associated with immune checkpoints and provide an opportunity for the treatment of advanced NSCLC patients with synthetic monoclonal antibodies. PD‐L1 expression is strictly associated with microRNA function in lung cancer cells. The group of microRNAs related to PD‐L1 includes, among others, miR‐200, miR‐197 or miRNA‐34. Expression of these molecules may be useful in lung cancer diagnosis, qualification to anti‐PD‐1 or anti‐PD‐L1 antibody therapy and could be a potential therapeutic target. However, studies on PD‐L1‐related microRNAs are necessary to develop advanced targeted molecular therapies.     

Immunosuppressive drugs affect interferon (IFN)‐γ and programmed cell death 1 (PD‐1) kinetics in patients with newly diagnosed autoimmune hepatitis

Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (T_regs). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in‐vitro effects of prednisolone, 6‐mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co‐inhibitory molecules and ability to proliferate of CD4⁺CD25^– cells, isolated from the peripheral blood of treatment‐naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)‐γ, interleukin (IL)‐17 and tumour necrosis factor (TNF)‐α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death‐1 (PD‐1), T cell immunoglobulin and mucin domain‐containing molecule‐3 (TIM‐3) and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) increase over 96‐h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN‐γ and PD‐1 expression in AIH, where control over CD4⁺CD25^– cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4⁺CD25^– cells more susceptible to T_reg control. Collectively, our data indicate that in treatment‐naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD‐1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to T_regs.     

PD‐1 modulates steady‐state and infection‐induced IL‐10 production in vivo

Programmed death‐1 (PD‐1) plays an important role in mediating immune tolerance through mechanisms that remain unclear. Herein, we investigated whether PD‐1 prevents excessive host tissue damage during infection with the protozoan parasite, Toxoplasma gondii. Surprisingly, our results demonstrate that PD‐1‐deficient mice have increased susceptibility to T. gondii, with increased parasite cyst counts along with reduced type‐1 cytokine responses (IL‐12 and IFN‐γ). PD‐1^?/? DCs showed no cell intrinsic defect in IL‐12 production in vitro. Instead, PD‐1 neutralization via genetic or pharmacological approaches resulted in a striking increase in IL‐10 release, which impaired type‐1‐inflammation during infection. Our results indicate that the absence of PD‐1 increases IL‐10 production even in the absence of infection. Although the possibility that such increased IL‐10 protects against autoimmune damage is speculative, our results show that IL‐10 suppresses the development of protective Th1 immune response after T. gondii infection.     

Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD‐L1 on dendritic cells

The mechanisms underlying Japanese encephalitis virus (JEV) pathogenesis need to be thoroughly explored to delineate therapeutic approaches. It is believed that JEV manipulates the innate and adaptive compartments of the host's immune system to evade immune response and cross the blood–brain barrier. The present study was thus designed to investigate the functional modulation of DCs after exposure to JEV and to assess the consequences on CD4⁺ T‐lymphocyte functions. Human monocyte‐derived DCs were either infected with 1 MOI of live virus, UV‐inactivated virus, or were mock‐infected. Replication‐competent JEV induced a significant increase in the expression of maturation markers 48 h postinfection, along with that of programmed cell death 1 ligand 1 (PD‐L1; also called B7‐H1 and CD274). JEV‐infected DCs expanded the Treg cells in allogenic mixed lymphocyte reactions. The expansion of Treg cells by JEV‐infected DCs was significantly reduced upon blocking PD‐L1 using an antagonist. In addition, JEV‐infected DCs significantly altered the proliferation and reduced the polarization of Th cells toward the Th1‐cell phenotype. The results, for the first time, suggest that JEV evades the host's immune system by modulating the crosstalk between DCs and T lymphocytes via the PD‐L1 axis.     

A study of PD‐L1 expression in intravascular large B cell lymphoma: correlation with clinical and pathological features

Intravascular large B cell lymphoma (IVLBCL) is a rare, aggressive, extranodal large B cell lymphoma characterised by growth of tumour cells within the lumen of vessels, particularly capillaries. Programmed cell death ligand 1 (PD‐L1) is a cell surface glycoprotein that interacts with programmed death 1 (PD‐1) on the T cell surface, leading to modulation of the immune response. PD‐L1 is a targetable immune check‐point molecule that is expressed on neoplastic cells in various cancers, including a subset of lymphomas. We correlated the expression of PD‐L1 with clinical and pathological findings in this rare disease. Eleven cases of IVLBCL were identified in the archives of Laboratory of Pathology at the National Cancer Institute, NIH. A panel of immunostains (CD20, CD3, CD5, PD‐L1) was performed. The cases were classified as the classic form or the variant associated with haemophagocytic syndrome (HPS) based on published 2017 WHO criteria. Three cases (27.3%) were HPS variant and eight cases (72.7%) were the classic form. Five (45.5%) of 11 cases were CD5‐positive; two of three (66%) were HPS variants and three of eight (37.5%) were classic form. Overall, four of nine evaluable cases (44.4%) were positive for PD‐L1, three of which were classic. Only one CD5‐positive case was PD‐L1‐positive, a classic variant. In summary, a subset of IVLBCL express PD‐L1. Although limited, these data suggest that PD‐L1 is expressed in both the so‐called classic form as well as the HPS variant. PD‐L1 is expressed irrespective of CD5 expression. Finally, detection of PD‐L1 expression in a subset of IVLBCL lymphoma cases may identify patients who might benefit from targeted immunotherapy.