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T Cell-Intrinsic PHD Proteins Regulate Pulmonary Immunity

Clever, David C, Clever
http://rave.ohiolink.edu/etdc/view?acc_num=osu1471868519

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Local immunity is an important feature of metastatic sites. Circulating tumor cells must evade secondary site immune responses for successful metastasis. The lung is a common metastatic site for numerous cancer types including malignant melanoma. While the diffuse pulmonary vascular architecture contributes to metastatic seeding, we hypothesized that organ-specific immunoregulatory mechanisms establish the lung as an immunologically permissive niche for tumor colonization. T lymphocytes play a critical role in coordinating organ-specific immune responses. Pulmonary T cell responses are restrained despite continuous exposure to innocuous foreign antigens. Excessive T cell effector activity within the pulmonary environment can result in adverse immune-mediated pathology. Thus, T cells must possess an intrinsic mechanism to sense their entry into the lungs and subsequently suppress responses against harmless self and foreign antigens. Consequently, however, such mechanisms might also repress T cell responses against infiltrating metastatic tumor cells. In the lung parenchyma T cells are exposed to localized concentrations of molecular oxygen (O2) as much as 2 to 3-fold higher than other lymphoid and non-lymphoid tissues. The prolyl-hydroxylase (PHD) family of proteins forms the cellular oxygen sensing machinery. We hypothesized that oxygen sensing by T cell-intrinsic PHD proteins coordinates an immunosuppressive program in the lung. Utilizing a mouse model with a T cell-specific deletion of all three PHD proteins (PHD-tKO), we found that T cell-intrinsic oxygen sensing is required to prevent mild autoimmune inflammation of the lungs. PHD proteins enable environmental oxygen to limit pulmonary type helper (Th)-1 responses, promote induction of CD4+-regulatory T (Treg) cells, and restrain CD8+ T cell effector differentiation and function in the steady state and following exposure to innocuous environmental antigens. Consequently, T cell-intrinsic PHD proteins establish the lung as an immunologically favorable metastatic niche and powerfully license colonization by circulating tumor cells. Tumor infiltration is accompanied by PHD protein-dependent induction of pulmonary Treg cells and suppression of IFN-γ-dependent tumor clearance. Strikingly, T cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung. Thus, the PHD proteins represent a novel therapeutic target to enhance anti-tumor T cell-mediated immunity. Adoptive cell transfer immunotherapy (ACT) is an emerging therapeutic strategy that harnesses the power of tumor specific T cells to mediate extensive tumor regression. Pharmacologic inhibition of PHD proteins using the small molecule DMOG promotes the effector capacity of tumor-specific CD4+ and CD8+ T cells. Importantly, following transfer into tumor bearing hosts, DMOG treated tumor-specific T cells mediated superior tumor regression at multiple sites of disease compared to control treated cells. Collectively, our results provide the first demonstration of an oxygen-dependent immunoregulatory program in the lung. We identify a non-redundant role for the oxygen-sensing PHD proteins in T cell biology. We also identify an immunological basis for preferential hematogenous metastasis of cancer cells to the lung and importantly elucidate a novel targetable pathway to enhance the efficacy of immune-based therapy by modulating the activity of the PHD proteins.
Schlesinger Larry, MD (Advisor)
Restifo Nicholas , MD (Committee Member)
Caligiuri Michael , MD (Committee Chair)
Byrd John, MD (Committee Member)
Benson Don, MD (Committee Member)
117 p.
Biomedical Research; Immunology
Tumor Immunology, Cancer Immunology, Immunotherapy, T cell differentiation, Pulmonary immunity, Mucosal immunology, Autoimmunity

Recommended Citations

Citations

  • Clever, Clever, D. C. (2016). T Cell-Intrinsic PHD Proteins Regulate Pulmonary Immunity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471868519

    APA Style (7th edition)

  • Clever, Clever, David. T Cell-Intrinsic PHD Proteins Regulate Pulmonary Immunity . 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1471868519.

    MLA Style (8th edition)

  • Clever, Clever, David. "T Cell-Intrinsic PHD Proteins Regulate Pulmonary Immunity ." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1471868519

    Chicago Manual of Style (17th edition)

osu1471868519
630
© 2016, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.