scholarly journals Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells

2005 ◽  
Vol 202 (7) ◽  
pp. 885-891 ◽  
Author(s):  
Kuibeom Ko ◽  
Sayuri Yamazaki ◽  
Kyoko Nakamura ◽  
Tomohisa Nishioka ◽  
Keiji Hirota ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Effector T Cells ◽  
Tumor Rejection ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Ifn Γ ◽  
Advanced Tumors

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family–related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-γ–secreting cells, infiltrated regressing tumors. Tumor-specific IFN-γ–secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-γ–intact mice but not IFN-γ–deficient mice. Furthermore, coadministration of anti-GITR and anti–CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg–specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg–mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-γ, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

Agonist anti-GITR antibody induces CD8 T cell-mediated tumor rejection

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3058-3058
Author(s):  
A. D. Cohen ◽  
A. Diab ◽  
M. A. Perales ◽  
F. Duan ◽  
R. Jenq ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Tumor Antigens ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Tumor Rejection ◽  
Cd8 Cells

3058 Background: Signaling through GITR (glucocorticoid-induced tumor necrosis factor receptor) can abrogate the suppressive effects of CD4+foxp3+ regulatory T cells and co-stimulate activated effector CD4+ and CD8+ T cells. We have previously shown that in vivo GITR ligation using the agonist anti-GITR mAb DTA-1 augments concomitant immunity and immunity generated by active immunization with self- tumor antigens. In the present study, we assessed the activity of anti-GITR mAb used alone, focusing on the effects of GITR ligation on CD8+ T cells during tumor growth. Methods: C57BL/6 mice were injected intradermally with B16 melanoma and received 1mg of DTA-1 or control rat IgG intraperitoneally on various days after tumor injection. In some experiments, naïve, CFSE-labeled pmel-1 CD8+ transgenic T cells (specific for the melanoma antigen gp10025–33 epitope) were transferred into naïve recipients 1 day prior to B16 inoculation. Results: DTA-1 treatment on days 0 and 4 led to tumor rejection in 20–30% and 50–60% of mice, respectively, compared with rejection in 0–5% of mice treated with control IgG (p<0.05 for both). Treatment at day 7 or later had no significant impact on tumor-free survival. The importance of CD8+ T cells in mediating DTA-1-induced tumor immunity was demonstrated by 4 findings: 1) in untreated mice, tumor-infiltrating CD8+ lymphocytes significantly upregulated GITR expression during tumor growth; 2) DTA-1-treated mice had greater CD8+ T cell infiltration into tumors than IgG-treated mice; 3) depletion of CD8+ cells completely abrogated the tumor protection provided by DTA-1; and 4) tumor-specific CD8+ cells proliferated more extensively, became more activated, and exhibited greater effector function following DTA-1 administration compared with control IgG. This was most dramatically seen within the tumor (compared with spleen or draining lymph node), suggesting that a major mechanism of tumor immunity induced by anti-GITR mAb may be overcoming impaired CD8+ T cell function within the tumor microenvironment. Conclusions: Ligating GITR using an agonist mAb can by itself augment tumor-specific CD8+ T cell responses and induce rejection of an aggressive, poorly immunogenic tumor. This strategy merits further consideration as an immune-modulating therapy for cancer. No significant financial relationships to disclose.

scholarly journals NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1342-1351 ◽  
Author(s):  
Zusen Fan ◽  
Ping Yu ◽  
Yang Wang ◽  
Yugang Wang ◽  
May Lynne Fu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Dependent Manner ◽  
Cd8 Cells ◽  
Ifn Γ

Natural killer (NK) cells are generally reported as innate effector cells for killing virally infected and transformed cells. It is unclear how NK cells evoke adaptive immunity to eradicate tumors. We now demonstrate that the TNF superfamily member, LIGHT, known as TNFSF14 and a T-cell costimulatory molecule, is a critical ligand for the activation of NK cells. Herpesvirus entry mediator (HVEM) is expressed on NK cells, and its engagement with LIGHT mediates NK-cell activation. The expression of LIGHT inside tumors leads to rapid rejection in a NK-dependent manner. Both NK and CD8+ cells are essential but not sufficient for the rejection of tumors because mice lacking either population fail to reject the tumor. Interestingly, activated NK cells do not kill tumors directly but can facilitate the priming of tumor-specific CD8+ T cells in an IFN-γ–dependent manner. Conversely, intratumor depletion of either NK cells or IFN-γ during tumor progression disrupts CD8+ cell–mediated tumor rejection, suggesting that the tumor is the essential site for the crosstalk between NK and CD8+ cells. Furthermore, IFNG-deficient NK cells fail to effectively activate CD8+ T cells, suggesting IFN-γ plays an important role in NK-mediated activation of cytotoxic T lymphocytes (CTLs). Our findings establish a direct role for LIGHT in NK activation/expansion and a critical helper role of activated NK cells in priming CD8+ T cells and breaking T-cell tolerance at the tumor site.

Dissociation of Systemic and Local Anti-Tumor Immunity Following Depletion of Regulatory T Cells Limits Therapeutic Activity in Established Tumors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 286-286
Author(s):  
Karl S. Peggs ◽  
Sergio A. Quezada ◽  
Tyler R. Simpson ◽  
James P. Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Clinical Studies ◽  
Cell Activity ◽  
Tumor Rejection ◽  
Tumor Challenge ◽  
Treg Depletion ◽  
Anti Tumor Activity

Abstract Interference with the inhibitory immunological checkpoints controlling T-cell activation provides new opportunities to augment cancer immunotherapies. CD4+CD25+Foxp3+ T cells (Treg) are important regulators of T cell activity being largely responsible for the maintenance of peripheral self-tolerance. Evidence for their role in fostering immune privilege within tumors has fueled attempts to manipulate their number or function for therapeutic benefit. In pre-clinical tumor models, CD25-directed Treg depletion efficiently synergizes with various immune-based approaches but only when depletion occurs prior or close to the time of tumor challenge. Accordingly, depletion in clinical studies has failed to consistently enhance immunostimulatory strategies. CTLA-4 is a cell-intrinsic inhibitor of T cell activity, and blocking antibodies enhance anti-tumor activity in both pre-clinical and clinical studies. Using in vivo murine models we combined a GM-CSF-secreting cellular vaccine (Gvax), CTLA-4-blockade and CD25-directed Treg depletion (using αCD25 monoclonal antibody either before [prophylactic] or after [therapeutic] tumor challenge) and studied their effects on systemic and local anti-tumor immunity. In contrast to prophylactic Treg depletion, therapeutic depletion failed to promote tumor rejection; this correlated with a lack of accumulation of T-cells within the tumor. Gvax/αCTLA-4 induced systemic accumulation of Treg which was prevented by Treg depletion regardless of its timing. Systemic anti-tumor responses were comparable as shown by similar T cell proliferation profiles and similar numbers of tumor-specific IFN-producing cells, suggesting that failure of therapeutic depletion to enhance rejection was unrelated to depletion of CD25+ effector T cells (Teff). Foxp3-directed depletion (in Foxp3-DTR mice) confirmed these findings. Similar effects in adoptively transferred antigen-specific transgenic CD8+ T cells verify the relevance of these data to tumor-specific T cells. Within the tumor, αCD25 drove mainly CD8+ T cells into cell cycle, compared to mainly CD4+Foxp3− T cells with Gvax/αCTLA-4. Combination had an additive effect, inducing the proliferation of the whole Teff compartment regardless of the timing of αCD25. Intra-tumoral Foxp3+ Treg were in cycle independent of therapy, suggesting a constant turnover. Given the similarities in systemic immunity and proliferative responses of the infiltrating populations regardless of αCD25 timing, but marked differences in the numbers of cells accumulating within the tumor, we focused on the possibility that differences in migration from the vascular compartment might explain our observations. Only prophylactic αCD25 led to expression of endothelial activation markers on tumor vasculature, which directly correlated with intra-tumoral T cell accumulation and tumor rejection. Importantly, systemic anti-tumor activity was transferable from mice receiving therapeutic depletion into tumor-bearing recipients after non-myeloablative conditioning, resulting in activation of the vascular endothelium, T cell infiltration and tumor rejection. Our data demonstrate the potential of vaccination strategies to induce counter-productive immuno-inhibitory host responses and reveal a dichotomy between systemic and local anti-tumor immunity following therapeutic Treg depletion. Finally, they support an alternative strategy for the treatment of established tumors in humans that exploits the augmented systemic immunity induced by vaccination following Treg depletion.

scholarly journals Tumor Rejection Induced by CD70-mediated Quantitative and Qualitative Effects on Effector CD8+ T Cell Formation

2004 ◽  
Vol 199 (11) ◽  
pp. 1595-1605 ◽  
Author(s):  
Ramon Arens ◽  
Koen Schepers ◽  
Martijn A. Nolte ◽  
Michiel F. van Oosterwijk ◽  
René A.W. van Lier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Formation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Dependent Manner ◽  
Ifn Γ

In vivo priming of antigen-specific CD8+ T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T cell response are programmed. However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-γ production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8+ T cell– and IFN-γ–dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

scholarly journals Induction of Mycobacterium tuberculosis-Specific Primary and Secondary T-Cell Responses in Interleukin-15-Deficient Mice

2005 ◽  
Vol 73 (5) ◽  
pp. 2910-2922 ◽  
Author(s):  
Vanja Lazarevic ◽  
David J. Yankura ◽  
Sherrie J. Divito ◽  
JoAnne L. Flynn
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Effector T Cells ◽  
Cell Responses ◽  
Interleukin 15 ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Several studies have provided evidence that interleukin-15 (IL-15) can enhance protective immune responses against Mycobacterium tuberculosis infection. However, the effects of IL-15 deficiency on the functionality of M. tuberculosis-specific CD4 and CD8 T cells are unknown. In this study, we investigated the generation and maintenance of effector and memory T-cell responses following M. tuberculosis infection of IL-15−/− mice. IL-15−/− mice had slightly higher bacterial numbers during chronic infection, which were accompanied by an increase in gamma interferon (IFN-γ)-producing CD4 and CD8 T cells. There was no evidence of increased apoptosis or a defect in proliferation of CD8 effector T cells following M. tuberculosis infection. The induction of cytotoxic and IFN-γ CD8 T-cell responses was normal in the absence of IL-15 signaling. The infiltration of CD4 and CD8 T cells into the lungs of “immune” IL-15−/− mice was delayed in response to M. tuberculosis challenge. These findings demonstrate that efficient effector CD4 and CD8 T cells can be developed following M. tuberculosis infection in the absence of IL-15 but that recall T-cell responses may be impaired.

scholarly journals Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

2006 ◽  
Vol 75 (3) ◽  
pp. 1154-1166 ◽  
Author(s):  
Laura H. Hogan ◽  
Dominic O. Co ◽  
Jozsef Karman ◽  
Erika Heninger ◽  
M. Suresh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacterial Load ◽  
Granulomatous Inflammation ◽  
Cd8 T Cell ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

148 Identification of prostate-restricted epithelial antigens for transgenic T cell adoptive therapy against prostate cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A161-A161
Author(s):  
Diana DeLucia ◽  
Tiffany Pariva ◽  
Roland Strong ◽  
Owen Witte ◽  
John Lee
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Adoptive Therapy ◽  
Mhc I ◽  
Epithelial Antigens ◽  
Ifn Γ ◽  
Stimulation Of

BackgroundIn advanced prostate cancer (PCa), progression to castration-resistant PCa (CRPC) is inevitable and novel therapies for CRPC are needed. Adoptive transfer of T cells targeting tumor antigens is a promising approach in the cancer field. Unfortunately, identifying antigens expressed exclusively in prostate tumor cells has been challenging. Since the prostate is not an essential organ, we alternatively selected prostate-restricted epithelial antigens (PREAs) expressed in both malignant and normal prostate tissue for transgenic T cell studies.MethodsRNA-seq data sets identifying genes enriched in PCa were cross-referenced with the NIH Genotype-Expression database to identify PREAs. Using a novel molecular immunology approach, select PREAs and major histocompatibility complex class I (MHC-I) molecules were co-expressed in HEK293F cells, from which MHC–peptide complexes were efficiently isolated. Peptides were eluted and sequenced by mass spectrometry. Peptide–MHC binding was validated with a T2 stabilization assay and peptide immunodominance was determined using an interferon-γ (IFN-γ) ELISpot assay following stimulation of healthy HLA-A2+ peripheral blood mononuclear cells (PBMC) with peptide pools. Following peptide stimulation, CD8+ T cells with peptide-specific T cell receptors (TCR) were enriched by peptide–MHC-I dextramer labeling and fluorescence activated cell sorting for single cell TCR α/β chain sequencing.ResultsWe identified 11 A2+ peptides (8 previously unpublished) from prostatic acid phosphatase (ACPP), solute carrier family 45 member 3 (SLC45A3), and NK3 homeobox 1 (NKX3.1) that bound to HLA-A2 with varying affinities. Extended culture stimulation of PBMC with peptide pools from each PREA, compared to the standard overnight culture, revealed a greater number of IFN-γ producing cells overall and a greater breadth of response across all the peptides. Antigen specific CD8+ T cells were detectable at low frequencies in both male and female healthy PBMC for 7 of the 11 peptides. Dextramer-sorted antigen-specific cells were used for single-cell paired TCR αβ sequencing and transgenic T cell development.ConclusionsThrough this work we identified HLA-A2-presented antigenic peptides from the PREAs ACPP, SLC45A3, and NKX3.1 that can induce the expansion of IFN-γ producing CD8+ T cells. Through peptide–MHC-I dextramer labeling, we isolated PREA-specific CD8+ T cells and characterized TCR αβ sequences with potential anti-tumor functionality. Our results highlight a rapid and directed platform for the development of MHC-I-restricted transgenic CD8+ T cells targeting lineage-specific proteins expressed in prostate epithelia for adoptive therapy of advanced PCa.

scholarly journals 323 Immunogenic syngeneic model MC38-OVA for the preclinical evaluation of immune evasion and checkpoint blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A348-A348
Author(s):  
Jessie Wang ◽  
Kaixia Lian ◽  
Jia Zheng ◽  
Chenpan Nie ◽  
Annie An ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Immune Evasion ◽  
Syngeneic Mouse ◽  
Ifn Γ ◽  
Draining Lymph Nodes ◽  
Syngeneic Tumors

BackgroundThe development of immuno-oncology (I/O) therapeutics has revolutionized the cancer treatment landscape. Despite this achievement, the mechanism behind limited responses is poorly understood. Tumor immune evasion has been reported to arise through the loss of tumor necrosis factor (TNF) signaling, interferon-γ (IFN-γ) signaling, and antigen presentation pathways, which are crucial to CD8+ T cell-mediated killing. Syngeneic mouse models have been widely used as they have an intact immune system, are easily accessible, and have a vast array of historical data for comparison. However, limited syngeneic models respond to immune checkpoint inhibitors, possibly due to low intrinsic immunogenicity. The expression of ovalbumin (OVA) has previously shown to sufficiently alter the susceptibility of syngeneic tumors to host T cell-mediated responses. In this study, the newly developed OVA-expressing MC38 syngeneic line was characterized for tumor immunity, checkpoint blockade response and response durability.MethodsMurine colon cancer MC38 cells were transduced by lentiviral vector with chicken OVA coding cDNA. A single clone was selected, and OVA expression was confirmed by western blot. The MC38-OVA cells were subcutaneously implanted into immunocompetent mice to evaluate the tumorigenicity and in vivo response to anti-PD-1 antibody treatment. Blood was collected 2 days post final dose of anti-PD-1 treatment for phenotypic analysis by FACS. Spleen and tumor draining lymph nodes were collected at termination for FACS analysis of IFN-γ+ T cells and OVA specific CD8+ T cells. Adoptive transfer was evaluated by challenge studies in both MC38-OVA and MC38 tumor-bearing mice with T cells derived from MC38-OVA mice, anti-PD-1 cured mice and OT-I mice. In vitro killing assays were performed to evaluate the function of adoptive CD3+ T cells transfer.ResultsOVA-expressing MC38 presented complete regression under anti-PD-1 treatment in vivo. T cell expansion was observed after anti-PD-1 treatment in peripheral blood with increased IFN-γ+ T cells in both tumor-draining lymph nodes and spleen. Additionally, anti-PD-1 cured mice generated robust tumor specific memory T cell, which successfully inhibited MC38-OVA and MC38 tumor growth following adoptive transfer. CD3+ T cells from MC38-OVA-bearing mice and OT-I mice showed anti-tumor immunity in vivo. In vitro killing assay demonstrated increased immunity.ConclusionsSyngeneic mouse tumor models are preferred preclinical models for I/O research, despite limited intrinsic immunogenicity. OVA expression in syngeneic tumors largely increased T cell-mediated immunity to enhance antigen-specific T cell responses during tumorigenesis, providing novel immunogenic models for preclinical immunotherapy evaluation.

scholarly journals 677 Reverse abscopal effect: intertumoral heterogeneity suppresses systemic CD8 T cell-mediated antitumor immunity and confers PD-1 inhibitor resistance in synchronous melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A705-A705
Author(s):  
Shuyang Qin ◽  
Booyeon Han ◽  
Alexander Chacon ◽  
Alexa Melucci ◽  
Alyssa Williams ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Abscopal Effect ◽  
Immunogenic Tumor ◽  
Ifn Γ

BackgroundDespite recent advancements in systemic therapy, only a minority of metastatic patients develop meaningful clinical responses to immune checkpoint inhibitors. Inherent genetic instability of melanoma generates genomically and microenvironmentally distinct metastases. These different tumor microenvironments (TMEs) contain numerous T cell suppression mechanisms, such as upregulation of the PD-1/PD-L1 exhaustion pathway. However, as synchronous metastases share one host immune system, intertumoral heterogeneity may result in increasing cross-talk between metastases that impairs systemic antitumor immunity and promotes PD-1 immunotherapy resistance.MethodsYUMM 1.7 (less immunogenic) and YUMMER 1.7 (more immunogenic cell line derived from YUMM following UVB irradiation) melanoma cell lines were simultaneously injected into opposite flanks of the same mice as a model of synchronous melanoma. We assessed tumor growth in wildtype, interferon-gamma (IFN-γ) knockout, and CD8-depleted mice as well as in response to PD-1 inhibitor. We characterized the TME with flow cytometry and performed TCR sequencing on tumor-infiltrating CD8 T cells.ResultsDistinct TMEs were observed for YUMM and YUMMER tumors simultaneously grown in the same mouse. The presence of the less immunogenic YUMM tumor allows the more immunogenic YUMMER tumors to escape IFN-γ and CD8 T cell-mediated rejection, despite abundant tumor-infiltrating, clonally expanded CD8 T cells. Identical immunodominant CD8 T cell clones were found in both YUMM and YUMMER tumors within the same mouse. Synchronous YUMMER-infiltrating CD8 T cells exhibit suppressed phenotypes, including increased persistence of surface PD-1 and decreased surface CD107a expressions. Simultaneously, these synchronous YUMMER tumors additionally upregulate macrophage surface PD-L1 expression, which potentially contributes to tumor immune escape. Lastly, synchronous YUMMER tumors become resistant to PD-1 inhibition, in direct contrast to control YUMMER tumors.ConclusionsIn a host with multiple melanoma lesions, immunogenicity of all tumors contribute to the systemic antitumor immune response. We show that two synchronous tumors with synonymous mutations (<40%), as is the case with metastatic patients, lead to skewed CD8 T cell expansion of the same clones in both tumors. The presence of a less immunogenic tumor prevents CD8 and IFN-γ mediated rejection of the more immunogenic tumor. Furthermore, CD8 T cells in the more immunogenic tumor exhibit decreased effector function and increased resistance to PD-1 blockade, as tumor-infiltrating macrophages concurrently become more immunosuppressive. These results are highly suggestive of a “reverse abscopal effect,” by which immunologically “cold” tumors generate systemic immunosuppression that facilitate PD-1 immunotherapy resistance and immune escape of all other tumors in synchronous metastatic melanoma patients.AcknowledgementsWe would like to thank Dr. Marcus Bosenberg from the Department of Dermatology at Yale University for kindly gifting us with the YUMMER 1.7 murine melanoma cell line.Ethics ApprovalAnimal experiments were approved by the University Committee on Animal Resources and performed in accordance with University of Rochester approved guidelines.

scholarly journals Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3948
Author(s):  
Kazumasa Oya ◽  
Yoshiyuki Nakamura ◽  
Zhu Zhenjie ◽  
Ryota Tanaka ◽  
Naoko Okiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Skin Lesions ◽  
Ifn Γ ◽  
Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

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