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  • The American Association of Immunologists  (7)
  • 1
    Online Resource
    Online Resource
    Anti-tumor immunity generated as an artifact of tumor implantation determines the response to immunotherapy in murine models
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 178.17-178.17
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 178.17-178.17
    Abstract: Cancer cell lines grown in vitro and implanted into mice are a centerpiece of preclinical modeling. However, tumor implantation is an in vivo vaccination event that can impact tumor growth. Checkpoint inhibitors targeting PD1 or CTLA4 interactions are effective at unleashing suppressed pre-existing immunity in murine models, but do not generate new immune responses. We hypothesized that tumor control by checkpoint inhibitor immunotherapies was dependent on pre-existing immunity generated at tumor implantation. Using cancer cells engineered to express model antigens, spontaneous tumor models with defined trackable antigens, or unmodified cancer cells, we demonstrate that tumor implantation results in initial T cell mediated immunity. As the tumors progress, these cells become undetectable in the periphery and accumulate in the tumor, but do not prevent tumor progression. While tumors respond to checkpoint inhibitors administered closely following implantation, delayed administration results in a loss of efficacy. This efficacy can be recovered by the addition of radiation therapy to checkpoint inhibitors, permitting cure of established murine tumors that are not controlled by either therapy alone. However, blocking the immune response at tumor implantation using a range of approaches results in a complete loss of efficacy of tumor control by all therapies based around checkpoint inhibitors. We demonstrate an approach to ‘silently’ establish tumors in mice to test therapies that can initiate de novo immunity to tumors. These data have significant implications for current clinical attempts to use checkpoint inhibitors, which may not be a solution for patients without pre-existing immunity to their tumor.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.178.17
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Loss of SOCS1 in dendritic cells increases dendritic cell maturation and decreases the CD8 T cell response to Listeria monocytogenes .
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 55.13-55.13
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 55.13-55.13
    Abstract: The suppressor of cytokine signaling (SOCS) family is a group of structurally related proteins characterized by a central SH2 domain that targets the SOCS proteins to specific molecules within the JAK-STAT pathway, and a SOCS-box domain that promotes degradation of the cytokine-receptor complex. SOCS-1 is induced by cellular activation and serves as a negative feedback mechanism for a range of cytokines. It has been described that silencing SOCS-1 in dendritic cells (DC) enhances antigen presentation, T cell priming, and anti-tumor immunity. Therefore, inhibition of SOCS-1 could profoundly augment the potency of the L. monocytogenes (Lm) based cancer vaccines that we are testing in clinical studies. We questioned the role of SOCS-1 in dendritic cells in vivo during intracellular infection, a scenario where antigen-specific T cells are required for microbial clearance. To test this we characterized the infection and immune response to Lm in CD11c-Cre × SOCS1fl/fl mice that have a SOCS1 deficiency in DC. DC lacking SOCS1 showed increased maturation in vivo at baseline, but showed equivalent responses to vaccination with DC-targeted antigens combined with α-CD40. We found that Lm can be recovered from spleens and livers from mice with SOCS1-deficient DC at similar levels to that of the wild type animals. However, mice with SOCS1-deficient DC showed a dramatic defect in the specific-CD8+ T cell response while the specific-CD4+ T cells response was not affected. The lack of CD8+ T cells response correlated with low levels of IFN-γ and MCP-1 in serum during the first days of infection and decreased NK maturation. Our results demonstrate that SOCS1 expression in DC is critical to generate a strong CD8 T cell response to Lm.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.55.13
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Tumor resident memory CD8 T cell formation and concomitant tumor immunity is CD40L dependent and CD4 independent.
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 63.02-63.02
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 63.02-63.02
    Abstract: The implantation of cancer cell lines into immunocompetent mice acts as a vaccination event, resulting in T cell immunity that impacts both tumor progression and the response to subsequent therapy. We have previously shown that blocking immunity at tumor implantation using anti-CD40L antibodies blocks development of an intratumoral antigen-specific CD8 T cell population with tissue resident memory (Trm) phenotypes, and also limits responsiveness to radiation therapy and immunotherapy combinations. Using pancreatic tumors derived from Pdx1-Cre and Pdx1-Cre /R26LSL-LSIY mice crossed with KrasLSL-G12D/+Tp53LSL-R172H/+ mice, we explored the role of CD4 T cells in providing CD40-CD40L help to generate Trm and conventional T central memory CD8 T cells (Tcm) cells in the tumor and systemically. Using depleting antibodies, we identified that Trm cells in the tumor could form independently of CD4 T cells but were lost following CD40L blockade. By contrast, systemically circulating Tcm cells that could re-expand after antigen-specific challenge were dependent on both CD4 T cells and CD40-CD40L interactions. Notably, concomitant immunity generated by tumor implantation that can prevent tumor growth on the opposite flank could also occur independently of CD4 T cells, but was lost on CD40L blockade. Systemic vaccination with Listeria monocytogenes expressing SIY efficiently induced the formation of SIY-specific Tcm cells but did not impact tumor implantation. These data suggest that tumor implantation generates Trm cells independently of CD4 T cells, and that these cells, not Tcm cells, sustain concomitant immunity. These data may impact immune therapies designed to control metastatic seeding in patients. Supported by grants from NIH (R01CA182311,  R01CA244142, R01CA208644).
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.63.02
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    Dendritic Cell Maturation Defines Immunological Responsiveness of Tumors to Radiation Therapy
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 12 ( 2020-06-15), p. 3416-3424
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 12 ( 2020-06-15), p. 3416-3424
    Abstract: Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated Ags. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor Ags, and migrate to the tumor draining lymph node to initiate cross-priming of tumor-reactive cytotoxic CD8+ T cells. In this study, we report that radiation therapy promotes the activation of intratumoral cDC1s in radioimmunogenic murine tumors, and this process fails to occur in poorly radioimmunogenic murine tumors. In poorly radioimmunogenic tumors, the adjuvant polyinosinic-polycytidylic acid overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1 and CD8+ T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and polyinosinic-polycytidylic acid significantly expands the proportion of proliferating CD8+ T cells in the tumor with enhanced cytolytic potential and requires T cell migration from lymph nodes for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly radioimmunogenic tumors, and coadministration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2000194
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Fluorescence tagging to monitor CD8 T cell recirculation from the tumor to the tumor-draining lymph node: the impact of focal radiation therapy on recirculation
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 118.04-118.04
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 118.04-118.04
    Abstract: T cells are continuously moving through tissues and recirculating back into the peripheral blood via lymph nodes. In cancer, tumor-specific T cells are enriched in the tumor environment and their presence is associated with improved outcome in patients and in preclinical models. T cells are known to contribute to tumor control following radiotherapy despite evidence indicating that radiation can be directly cytotoxic to lymphocytes. The impact of radiation therapy on recirculation of T cells through the tumor to the tumor draining lymph node (TDLN) and their trafficking to distant sites is unclear. By photoconverting tumor infiltrating cells using focal UV in Kaede mice we can use fluorescence tagging to directly identify T cells in the TDLN that originated in the tumor. We demonstrate that radiation therapy significantly decreases CD8 T cell trafficking from the tumor to the TDLN. Using single cell RNASeq and flow cytometry, we demonstrate that radiation therapy is locally cytotoxic to proliferating effector CD8 T cells within the tumor environment. This results in the loss of this effector population in the TDLN following treatment. Using flow cytometry and direct blockade of T cell entry into the LN, we characterize the CD8 T cells in the TDLN that proliferate following radiation therapy. Our data demonstrate that radiation therapy is locally cytotoxic and restricts CD8 T cell recirculation to the TDLN. Since tumor control following radiation therapy is partially dependent on CD8 T cell responses, these data force us to re-evaluate both the type and location of T cell populations that contribute to tumor control following radiation therapy. Supported by grants from the NIH (R01CA182311, R01CA244142, R01CA208644)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.118.04
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Amplifying IFN-γ Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1 ( 2018-01-01), p. 177-185
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1 ( 2018-01-01), p. 177-185
    Abstract: Although prophylactic vaccines provide protective humoral immunity against infectious agents, vaccines that elicit potent CD8 T cell responses are valuable tools to shape and drive cellular immunity against cancer and intracellular infection. In particular, IFN-γ–polarized cytotoxic CD8 T cell immunity is considered optimal for protective immunity against intracellular Ags. Suppressor of cytokine signaling (SOCS)1 is a cross-functional negative regulator of TLR and cytokine receptor signaling via degradation of the receptor–signaling complex. We hypothesized that loss of SOCS1 in dendritic cells (DCs) would improve T cell responses by accentuating IFN-γ–directed immune responses. We tested this hypothesis using a recombinant Listeria monocytogenes vaccine platform that targets CD11c+ DCs in mice in which SOCS1 is selectively deleted in all CD11c+ cells. Unexpectedly, in mice lacking SOCS1 expression in CD11c+ cells, we observed a decrease in CD8+ T cell response to the L. monocytogenes vaccine. NK cell responses were also decreased in mice lacking SOCS1 expression in CD11c+ cells but did not explain the defect in CD8+ T cell immunity. We found that DCs lacking SOCS1 expression were functional in driving Ag-specific CD8+ T cell expansion in vitro but that this process was defective following infection in vivo. Instead, monocyte-derived innate TNF-α and inducible NO synthase–producing DCs dominated the antibacterial response. Thus, loss of SOCS1 in CD11c+ cells skewed the balance of immune response to infection by increasing innate responses while decreasing Ag-specific adaptive responses to infectious Ags.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700909
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    3D co-culture models demonstrate radiation-mediated activation of tumor-associated macrophages
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 169.04-169.04
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 169.04-169.04
    Abstract: Type I IFN signaling mediated by STING pathway is important for the induction of radiation-stimulated adaptive immune responses in responsive tumors. Macrophages recruited to tumors following radiotherapy (RT) can influence the response to RT. Reprogramming immunosuppressive M2-like macrophages in tumors to exhibit a more activated M1-like phenotype can help improve response to therapies. Here, we hypothesize that a 3D co-culture model of cancer cells and macrophages will be more contextually relevant to the events occurring in tumors and can be used to study the crosstalk that occurs between these cells in vivo. We initially optimized seeding densities of murine MC38 colorectal carcinoma cells to develop spheroids of consistent size. Using GFP+ macrophages and Hoechst stained MC38, we imaged the development and localization of these cells during spheroid formation. Next, co-culture spheroids were exposed to 12 Gy radiation on day 1. Viability and phenotype of macrophages in spheroid co-cultures was assessed on day 4 using flow cytometry by staining for CD80, CD86, MHC Class II, CD69 and CD206 expression. STING ligand, cyclic di-AMP (CDA) treated spheroid co-cultures were used as positive controls. CDA treatment significantly increased CD80/86 expression in 3D co-cultures. Treatment with 12 Gy radiation showed similar effect. Interestingly, macrophages derived from MyD88 Lyz2Cre, MyD88 fl/fland STING knockout mice also showed a significant increase in CD80/86 and CD40, suggesting that macrophage activation was independent of MyD88 or STING signaling. Ongoing studies aim to explore the pathways activated on irradiation in these cells and further cross-validate with the macrophage phenotypes observed in vivo in response to RT.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.169.04
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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