KS01.4.A NK cells as key orchestrators in mediating the anti-tumour response to immune checkpoint blockade in melanoma brain metastases

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii3-ii3
Author(s):  
C M Fife ◽  
J Williams ◽  
R Brownlie ◽  
T Andreou ◽  
A Sunderland ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Brain Metastases ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Cell Depletion

Abstract BACKGROUND Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have demonstrated efficacy against melanoma BrM. Despite this, therapeutic responses are highly variable, and it is unknown why therapy fails in a high proportion of patients. Improved therapeutic strategies require a thorough understanding of potentially exploitable mechanisms of therapeutic efficacy. Our data previously implicated different immune cells, foremost CD8+ T cells, but also NK cells, in the intracranial efficacy and enhanced survival benefit of immune checkpoint blockade (ICB). Our aim here is to investigate the role of NK cells in mediating the response to ICB in melanoma BrM. MATERIAL AND METHODS To study the role of NK cells in the response to ICB in melanoma BrM, a tumour transplantation model of B16 melanoma with simultaneous extracranial (i.e., flank) and brain tumours in C57BL/6 mice was utilised. NK cells were depleted through administration of anti-asialo-GM1 NK cell-depleting antibodies. Confirmation of NK cell depletion and quantification of intratumoral immune cell populations was performed using flow cytometry. Intratumoral gene expression of key chemokines and immune mediator genes was assessed using RT-qPCR and mRNA-seq. RESULTS Highly variable response to ICB with respect to intratumoral accumulation of CD8+ T cells allowed separation of mice into responders and non-responders and revealed genes and pathways associated with response to ICB. NK cell depletion reversed the ICB-mediated increase in the accumulation of CD8+ T cells and significantly reduced the expression of genes associated with response in intracranial and extracranial tumours. The ICB-mediated significant increase in gene expression of various chemokines (i.e., Cxcl9/10) and immune mediators (i.e., Ifng, Prf1 and Gzmb) was significantly abrogated upon NK cell depletion. CONCLUSION NK cells play a critical role in the underlying mechanisms of ICB efficacy through their modulation of the tumour microenvironment and enhancement of CD8+ T cell accumulation in intracranial tumours. Targeting of NK cells may allow potentiation of ICB therapy in the brain, as well as at extracranial sites.

Donor’s NK Cells May Influence the Engraftment in Pediatrics Patients after T-Cell Depleted Haploidentical Stem Cell Transplant for Thalassemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4595-4595
Author(s):  
Antonella Isgro ◽  
Marco Marziali ◽  
Pietro Sodani ◽  
Javid Gaziev ◽  
Paola Polchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Hla Class I ◽  
Mixed Chimerism ◽  
Effector Cells ◽  
Post Transplant

Abstract In haploidentical hematopoietic transplantation, donor-versus-recipient NK cell alloreactivity derives from a mismatch between donor NK clones bearing inhibitory Killer Cell Ig-like Receptors (KIRs) for self HLA class I molecules and their HLA class I ligands (KIR ligands) on recipient cells. The mechanism whereby alloreactive NK cells exert their benefits in transplantation has been elucidated. The infusion of alloreactive NK cells ablates recipient T cells which reject the graft, and ablates recipient dendritic cells (DCs) which trigger GvHD, thus protecting from GvHD (Ruggeri et al., Science 2002). NK cell alloreactivity also boosts very rapid rebuilding of donor adaptive immunity to infections. In this study we analysed the potential role of NK cells after haploidentical transplant in b-thalassemia patients. T and B cell depletion was carried out with CD34+ coated magnetic microbeads and the CliniMACS device (Miltenyi Biotec©) from peripheral blood and bone marrow of donors (the mothers) and resulted in grafts consisting of stem cells and effector cells (NK cells, monocytes) with the addition of bone marrow mononuclear cells (BMMNCs 3 × 105/kg of the recipient). A total of 11 pediatric patients with b-thalassemia received T and B cell depleted transplants from their haploidentical mothers with a median number of 15 ×106 CD34 stem cells. To analyse the mechanisms involved in immunological reconstitution post transplant, we analysed T cell subsets by flow cytometry, particularly NK sets (CD3- CD56+, CD3− CD16+ and CD56+CD16+ NK cells) at day + 20 and + 60 post transplant. Day + 20 post transplant, the patients had significantly lower CD4+ T cells in comparison to the controls (1.9 ± 1.4% vs. 47.5 ± 6% respectively), whereas CD8+ T cells numbers did not statistically differ between patients and controls (24.2 ± 33.7% vs. 20 ± 7%). NK cells were among the first lymphocytes to repopulate the peripheral blood, and up to 70% of these cells were CD3-CD56+bright cells. Interestingly, a direct correlation has been observed between the percentages of CD56+CD16+ NK subset and the BM engraftment (in mean 71 ± 21% CD56+CD16+ in the four patients with full engraftment, 27 ± 28% in the three patients with a stable mixed chimerism after BM transplant (70–80% of donor cells) and 1.4 ± 1% in the four patients with rejection). In all the patients the origin of the NK subsets was from the mothers. Day + 60 post transplant an increase in the percentages of CD4+ T cells, naïve CD4+ cells and in thymic naïve Th cells were observed (3 ± 1.2%, 2.9 ± 2.1%, 2.7 ± 1%, respectively). CD8+ T cells were also increased (in mean 35 ± 27.5%), in parallel with the increase of the CD3-CD16+ NK cells (potent cytotoxic effector cells) especially in the patients with full engraftment (in mean 47 ± 20% vs. 28 ± 31% in mixed chimerism) NK CD56+bright cells develop more rapidly than other lymphocytes, but CD16+ NK cells (with cytotoxic potential) require more prolonged exposure to maturation factor (IL-2) in the bone marrow. Interestingly we observed higher percentages of NK subsets just twenty days post transplant in the patients with full engraftment respect the mixed chimerism and the rejection, suggesting a role of donor NK cells on improved engraftment and on prevention of the rejection with the attack of the host lympho-hematopoietic cells. These observations may suggest the importance of NK subsets analyses at the first time of the transplant as an useful parameter for the outcome of the transplant and/or the use of donor’s alloreactive NK cells especially in haploidentical recipients.

Targeting CD137 to enhance the antitumor efficacy of cetuximab by stimulation of innate and adaptive immunity.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3015-3015 ◽  
Author(s):  
Holbrook Edwin Kohrt ◽  
Roch Houot ◽  
Kipp Weiskopf ◽  
Matthew Goldstein ◽  
Peder Lund ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adaptive Immunity ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cell Depletion ◽  
Innate And Adaptive Immunity ◽  
Cetuximab Therapy

3015 Background: Cetuximab therapy results in beneficial, yet limited, clinical improvement for patients with KRAS wildtype (WT) colorectal (CRC) and head and neck (HN) cancer. The efficacy of cetuximab, an IgG1 monoclonal antibody against EGFR, is due in part to antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. CD137 is a costimulatory molecule expressed following activation on NK and memory, antigen-specific, CD8 T cells. Methods: We investigated the hypothesis that the combination of cetuximab with anti-CD137 mAb will enhance innate and adaptive immunity, thereby improving cetuximab’s anti-tumor efficacy in preclinical models and a prospective trial, NCT01114256. Results: NK cells increased their expression of CD137 by a factor of 30-40 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. An agonistic anti-CD137 mAb enhanced NK cell degranulation and cytotoxicity 2-fold (~45 to 90% tumor lysis assayed by chromium release). The combination of cetuximab and anti-CD137 mAbs was synergistic in a syngeneic, human-EGFR-transfected murine tumor leading to complete tumor resolution and prolonged survival. NK cell depletion, significantly, and CD8 T cell depletion, partly, abrogated the anti-tumor efficacy of this combination. A series of HN and both KRAS WT and mutant CRC xenotransplant models demonstrated synergy with cetuximab and anti-CD137 mAbs. In our clinical trial, 54 patients with HN cancer receiving cetuximab therapy, circulating and intratumoral NK cells upregulated CD137 with amplitude influenced by duration post-cetuximab and host FcyRIIIa polymorphism. Interestingly, in 10 HLA-A2+ patients, following cetuximab, an increase in EGFR-specific, CD137-expressing, CD8 T cells directly correlated with the percent increase in CD137-expressing NK cells. Conclusions: Our results demonstrate the synergy of combining an agonistic mAb, anti-CD137, augmenting ADCC and T cell memory following a tumor-targeting mAb, cetuximab, in HN and KRAS mutant and WT CRC cancer. These results support a novel, sequential antibody approach by targeting first the tumor and then the host innate and adaptive immune system. Clinical trial information: NCT01114256.

scholarly journals Therapy of lymphoma by immune checkpoint inhibitors: the role of T cells, NK cells and cytokine-induced tumor senescence

2021 ◽  
Vol 9 (1) ◽  
pp. e001660
Author(s):  
Fatima Ahmetlic ◽  
Josia Fauser ◽  
Tanja Riedel ◽  
Vera Bauer ◽  
Carolin Flessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Ifn Γ

BackgroundAlthough antibodies blocking immune checkpoints have already been approved for clinical cancer treatment, the mechanisms involved are not yet completely elucidated. Here we used a λ-MYC transgenic model of endogenously growing B-cell lymphoma to analyze the requirements for effective therapy with immune checkpoint inhibitors.MethodsGrowth of spontaneous lymphoma was monitored in mice that received antibodies targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein-4, and the role of different immune cell compartments and cytokines was studied by in vivo depletion experiments. Activation of T and natural killer cells and the induction of tumor senescence were analyzed by flow cytometry.ResultsOn immune checkpoint blockade, visible lymphomas developed at later time points than in untreated controls, indicating an enhanced tumor control. Importantly, 20% to 30% of mice were even long-term protected and did never develop clinical signs of tumor growth. The therapeutic effect was dependent on cytokine-induced senescence in malignant B cells. The proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor (TNF) were necessary for the survival benefit as well as for senescence induction in the λ-MYC model. Antibody therapy improved T-cell functions such as cytokine production, and long-time survivors were only observed in the presence of T cells. Yet, NK cells also had a pronounced effect on therapy-induced delay of tumor growth. Antibody treatment enhanced numbers, proliferation and IFN-γ expression of NK cells in developing tumors. The therapeutic effect was fully abrogated only after depletion of both, T cells and NK cells, or after ablation of either IFN-γ or TNF.ConclusionsTumor cell senescence may explain why patients responding to immune checkpoint blockade frequently show stable growth arrest of tumors rather than complete tumor regression. In the lymphoma model studied, successful therapy required both, tumor-directed T-cell responses and NK cells, which control, at least partly, tumor development through cytokine-induced tumor senescence.

CD8+ T Cells Mediate Antibody-Independent Platelet Clearance Following Transfusion

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 596-596
Author(s):  
Seema R Patel ◽  
Connie M Arthur ◽  
Lilian Rodrigues ◽  
Carol Xue ◽  
James C. Zimring ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cellular Immunity ◽  
Cd8 T Cells ◽  
Platelet Transfusion ◽  
Nk Cell ◽  
Cell Depletion ◽  
Solid Organ ◽  
Mhc Antigens ◽  
Immune Mediated

Abstract Background: Alloimmunization to major histocompatibility complex (MHC) antigens is the leading immunological barrier to transplantation and platelet transfusion therapy. In the context of platelet transfusion medicine, alloimmunization to MHC antigens can substantially diminish the therapeutic efficacy of subsequent blood transfusions. Presently, MHC alloantibodies are recognized as the primary mediators of immune-mediated platelet clearance. However, individuals previously exposed to MHC alloantigens can display significant platelet clearance in the absence of detectable anti-platelet antibodies. Given the ability of cellular immunity to mediate rejection of solid organ allografts across MHC differences, we hypothesized that cellular immunity likewise facilitates the clearance of platelets in MHC alloimmunized recipients. Methods: FVB (H-2Kq) MHC-immunized or non-immunized C57BL/6 (H-2Kb) recipients were transfused with filter leukoreduced platelet rich plasma (PRP) isolated from C57BL/6 donors expressing green fluorescent protein (GFP) under a H-2Kb promoter (B6 GFP) or PRP obtained from a FVB X B6 GFP F1 cross, which generates GFP+ H-2Kq+ platelets. Following transfusion, mice were bled at 10 minutes, 1 hour, 2 hours or 24 hours to calculate the percentage of GFP+ transfused platelets remaining using flow cytometric analysis. To test the hypothesis that platelet clearance can occur in an antibody-independent process, FVB H-2Kq MHC-immunized or non-immunized μMT recipients were similarly transfused with B6 GFP or FVB X B6 GFP PRP. CD8+ T cells in immunized μMT recipients were depleted by i.p. injection of anti-CD8 (clone 2.43) antibody for 3 consecutive days prior to transfusion. NK cells were similarly depleted by injection of anti-NK1.1 (clone PK-136) antibody, 1 day prior to transfusion. CD4, CD8 T cell and NK cell depletion was evaluated in the peripheral blood prior to platelet transfusion, and compared to non-treated and isotype control treated recipients. Results: While GFP+ platelets were readily detected following transfusion into non-immunized or MHC matched recipients, transfusion of FVB-B6 platelets into H-2Kq MHC-immunized C57BL/6 recipients resulted in rapid clearance within the first hour following transfusion. In contrast, though little platelet clearance was detected in H-2Kq MHC-immunized μMT recipients within an hour following transfusion, very few transfused platelets were observed after 24 hours. Moreover, despite platelet clearance, anti-MHC antibodies were not detectable in μMT recipients. To determine the cellular component responsible for clearance in alloimmunized μMT recipients, CD8+ T cells or NK cells were depleted prior to transfusion. NK cell depletion failed to impact platelet clearance in alloimmunized μMT recipients; however, depletion of CD8+ T cells prior to platelet transfusion abrogated platelet clearance in immunized μMT recipients. Conclusion: Immunized recipients rapidly clear platelets in an alloantigen specific fashion following platelet transfusion in a murine model. Though platelet clearance occurred at a faster rate in intact immunized C57BL/6 recipients, B cell deficient MHC-immunized μMT recipients possessed the capacity to induce significant clearance at later time points. Evaluation of the cellular populations responsible for antibody-independent clearance in μMT recipients strongly suggest that CD8+ T cells play a key role in antibody-independent immune-mediated platelet clearance. These results suggest that, in addition to antibodies, CD8+ T cells can play a role in the development of platelet refractoriness and may contribute to platelet non-responsiveness in patients with little to no detectable anti-platelet alloantibodies. Disclosures No relevant conflicts of interest to declare.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

2005 ◽  
Vol 18 (2) ◽  
pp. 269-276 ◽  
Author(s):  
F. Martini ◽  
C. Agrati ◽  
G. D'Offizi ◽  
F. Poccia
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Treatment Interruption ◽  
Cell Number ◽  
Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

scholarly journals Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2762 ◽  
Author(s):  
Xinrui Zhao ◽  
Chunlin Shao
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Combined Therapy ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Abscopal Effect ◽  
Specific Circumstance

Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the “hot” tumors gradually turn to “cold”. With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic.

scholarly journals Role of tumor gene mutations in treatment response to immune checkpoint blockades

2019 ◽  
Vol 2 (2) ◽  
pp. 100-109 ◽  
Author(s):  
Manni Wang ◽  
Liu Yu ◽  
Xiawei Wei ◽  
Yuquan Wei
Keyword(s):  
Gene Expression ◽  
Treatment Response ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Gene Mutations ◽  
Immune Checkpoint Blockade ◽  
Recent Developments ◽  
Tumor Gene

AbstractEarly studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment, with later studies applying immune checkpoint blockade (ICB) in treatment of various malignancies. Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients, the treatment response varies. Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response. Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment. In this review, we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells, which it is hoped will help to optimize the clinical application of ICBs in cancer patients.

scholarly journals Comprehensive analysis of cutaneous and uveal melanoma liver metastases

2020 ◽  
Vol 8 (2) ◽  
pp. e001501
Author(s):  
Esmee P Hoefsmit ◽  
Elisa A Rozeman ◽  
Trieu My Van ◽  
Petros Dimitriadis ◽  
Oscar Krijgsman ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Liver Metastases ◽  
Uveal Melanoma ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Metastatic Site ◽  
Immune Infiltration

BackgroundThe profound disparity in response to immune checkpoint blockade (ICB) by cutaneous melanoma (CM) and uveal melanoma (UM) patients is not well understood. Therefore, we characterized metastases of CM and UM from the same metastatic site (liver), in order to dissect the potential underlying mechanism in differential response on ICB.MethodsTumor liver samples from CM (n=38) and UM (n=28) patients were analyzed at the genomic (whole exome sequencing), transcriptional (RNA sequencing) and protein (immunohistochemistry and GeoMx Digital Spatial Profiling) level.ResultsComparison of CM and UM metastases from the same metastatic site revealed that, although originating from the same melanocyte lineage, CM and UM differed in somatic mutation profile, copy number profile, tumor mutational burden (TMB) and consequently predicted neoantigens. A higher melanin content and higher expression of the melanoma differentiation antigen MelanA was observed in liver metastases of UM patients. No difference in B2M and human leukocyte antigen-DR (HLA-DR) expression was observed. A higher expression of programmed cell death ligand 1 (PD-L1) was found in CM compared with UM liver metastases, although the majority of CM and UM liver metastases lacked PD-L1 expression. There was no difference in the extent of immune infiltration observed between CM and UM metastases, with the exception of a higher expression of CD163 (p<0.0001) in CM liver samples. While the extent of immune infiltration was similar for CM and UM metastases, the ratio of exhausted CD8 T cells to cytotoxic T cells, to total CD8 T cells and to Th1 cells, was significantly higher in UM metastases.ConclusionsWhile TMB was different between CM and UM metastases, tumor immune infiltration was similar. The greater dependency on PD-L1 as an immune checkpoint in CM and the identification of higher exhaustion ratios in UM may both serve as explanations for the difference in response to ICB. Consequently, in order to improve current treatment for metastatic UM, reversal of T cell exhaustion beyond programmed cell death 1 blockade should be considered.

scholarly journals Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

2019 ◽  
Vol 11 (501) ◽  
pp. eaav7816 ◽  
Author(s):  
Rachael M. Zemek ◽  
Emma De Jong ◽  
Wee Loong Chin ◽  
Iona S. Schuster ◽  
Vanessa S. Fear ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Poly I:C ◽  
Mouse Strains

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line–derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti–IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.

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