Randall S. Johnson

Randall S. Johnson

Professor, Kallad
E-postadress: randall.johnson@ki.se
Telefon: +46852487329
Besöksadress: Solnavägen 9, 17165 Stockholm
Postadress: C5 Cell- och molekylärbiologi, C5 CMB Johnson, 171 77 Stockholm
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Om mig

  • Randall S. Johnson är professor i molekylär biologi och hypoxins biologi vid institutionen för cell- och molekylärbiologi. Hypoxi är en medicinsk term som betyder att kroppens vävnader lider av syrebrist. Cancertumörer klarar sig vanligen med mindre syre än frisk vävnad och Randall S Johnssons forskning handlar om olika aspekter av detta.

Artiklar

Alla övriga publikationer

Forskningsbidrag

  • Swedish Research Council
    1 January 2023 - 31 December 2026
    In this project we will build on the previous support we have received from Vetenskapsrådet that has allowed us to establish that increasing the capacity for hypoxic response in cytotoxic T cells in turn increases their immunotherapeutic efficacy. We have shown that increased expression of the transcription factor HIF via both retroviral vectors in mouse cells and CAR T vectors in human donor T cells can increase the capacity of CD8+ T cells to kill target tumor cells and reduce tumor growth in vivo. In the case of the CAR vectors, this increase can even be curative.We propose to continue these studies so as to prepare for a clinical trial of our findings. As part of this preparation, we describe work to characterise the metabolic effects of the alterations in T cells induced by overexpression of HIF vectors, wherein we will correlate those changes with metabolic aspects of central memory and effector T cells. We will use this information to establish how HIF acts to improve cytotoxic efficacy and T cell persistence in vivo. We also propose to study how hypoxic culture of T cells ex vivo, or treatment with inducers of HIF expression, could act to improve efficacy of current CAR therapies being used in the clinic today. Finally, we propose to characterise the broader relevance of our findings to solid tumors beyond lymphomas, and ask whether increasing HIF can increase the potential use of CAR and other immunotherapies in a wider range of malignancies.
  • Barncancerfonden
    1 January 2023 - 31 December 2023
  • Swedish Cancer Society
    1 January 2022
    T cells are an important part of our immune system, and also have a large role in current cancer therapies. Tumors often have parts that are almost completely devoid of oxygen, due to their chaotic structure. A T cell that is to attack a tumor in an immunotherapeutic context must be able to handle very low levels of oxygen. We have discovered that if we give T cells a genetically enhanced ability to adapt to oxygen deprivation, they become much more effective. We now want to further understand the basic principles behind this discovery, and use them to improve immunotherapy against cancer. The project is about how we can improve the immune system against cancer. We know that it is difficult for an immune cell to get into some tumors, because they have very little oxygen due to a chaotic network of vessels. If we give T cells a better ability to deal with a lack of oxygen, we now know that they are much better at attacking and killing cancer cells. We want to gain a better understanding of this phenomenon, so that we can then use T cell immunotherapy against many more types of cancer than is currently possible. An improved and expanded immunotherapy. We want certain therapies that are now only effective in certain cases and in certain cancer types to be able to be developed so that they can be used much more often. We believe that even a better understanding of how much oxygen T cells need when they are grown in the clinic before they are used in the clinic can lead to great improvements and an increased effectiveness of these treatments.
  • Metabolic and epigenetic regulation of cancer associated fibroblasts by angiotensin II
    Canadian Institutes of Health Research
    1 June 2021 - 31 August 2024
  • Canadian Institutes of Health Research
    1 June 2021 - 31 May 2025
  • Swedish Research Council
    1 January 2020 - 31 December 2022
  • Oxygen and immune response
    Wellcome Trust Ltd
    1 January 2019 - 31 July 2024
  • Acute deficiency and activation of the immune system in cancer
    Swedish Cancer Society
    1 January 2018
    We have discovered that there are dimensions to shifts in tumor oxygenation that give rise to opposing roles for the response to oxygen loss. Some immune cells repress immune response when oxygen levels are low, whereas other immune cells, including those that kill tumors, require oxygen to function. This proposal will determine how best to understand and potentially balance these responses to better treat cancer. The project is focussed on determining how the response to shifts in oxygenation affect immune cells during cancer treatment, in particular immunotherapeutic treatments. We hope to find methods to greatly improve the efficacy of immunotherapies for the increasing number of cancers that are being treated with manipulated immune cells.
  • Swedish Research Council
    1 January 2017 - 31 December 2019
  • Acute deficiency and inflammation in prognosis and treatment of breast cancer
    Swedish Cancer Society
    1 January 2016
    In almost all cases, mortality in breast cancer is due to the tumor being spread - metastasized - to other tissues. If a tumor is to metastasize, it depends largely on how the environment in the tumor looks. In breast cancer, inflammation and low oxygen availability are two factors with strong links to increased risk of spreading and reduced survival. Because it is known that the immune system cells - depending on how they are activated - can either counteract the development of the tumor or have an active part in how tumor cells are spread, we intend to investigate whether and how the combination of inflammation and lack of oxygen affects tumor growth and spread. In the case of oxygen deficiency, the response of the cells is largely regulated by Hypoxia Inducible Factor (HIF). Like oxygen deficiency, high levels of HIF-1 are also linked to poor prognosis in breast cancer. We have previously shown that the formation of metastases in animal models decreases markedly when the cancer cells lack HIF-1. Now we want to investigate how low oxygen availability and HIF make immune cells able to counteract the tumor or contribute to the spread. This is done by removing HIF from known populations of immune cells and using mouse models for breast cancer that have known spread patterns and, as far as possible, mimic the situation humanly. We are looking for a deeper understanding of how the oxygen deficiency prevailing in the tumor affects the immune system and why it is so strongly linked to prognosis in breast cancer. We therefore want to be able to contribute to optimizing treatment strategies that limit the risk of spreading from the primary tumor while maintaining and strengthening an immune system that actively counteracts the growth of the tumor cells.
  • Swedish Research Council
    1 January 2016 - 31 December 2018
  • Acute deficiency and inflammation in prognosis and treatment of breast cancer
    Swedish Cancer Society
    1 January 2015
    In almost all cases, mortality in breast cancer is due to the tumor being spread - metastasized - to other tissues. If a tumor is to metastasize, it depends largely on how the environment in the tumor looks. In breast cancer, inflammation and low oxygen availability are two factors with strong links to increased risk of spreading and reduced survival. Because it is known that the immune system cells - depending on how they are activated - can either counteract the development of the tumor or have an active part in how tumor cells are spread, we intend to investigate whether and how the combination of inflammation and lack of oxygen affects tumor growth and spread. In the case of oxygen deficiency, the response of the cells is largely regulated by Hypoxia Inducible Factor (HIF). Like oxygen deficiency, high levels of HIF-1 are also linked to poor prognosis in breast cancer. We have previously shown that the formation of metastases in animal models decreases markedly when the cancer cells lack HIF-1. Now we want to investigate how low oxygen availability and HIF make immune cells able to counteract the tumor or contribute to the spread. This is done by removing HIF from known populations of immune cells and using mouse models for breast cancer that have known spread patterns and, as far as possible, mimic the situation humanly. We are looking for a deeper understanding of how the oxygen deficiency prevailing in the tumor affects the immune system and why it is so strongly linked to prognosis in breast cancer. We therefore want to be able to contribute to optimizing treatment strategies that limit the risk of spreading from the primary tumor while maintaining and strengthening an immune system that actively counteracts the growth of the tumor cells.
  • Hypoxia and inflammation in the spread of breast cancer.
    Swedish Cancer Society
    1 January 2014
    In Sweden, about 7,000 women each year are affected by breast cancer. In almost all cases, mortality in breast cancer depends on the tumor having metastasized to other tissues. If a tumor is to metastasize, it depends largely on how the environment in the tumor looks. In breast cancer, inflammation and low oxygen availability are two factors with strong links to increased risk of spreading and reduced survival. When a tumor grows, areas of oxygen deficiency often occur as a result of poor blood vessels and limited blood supply. Poor oxygen availability can affect a tumor in two ways
    partly by causing changes in the tumor cells that can make them more prone to spread and increase the risk of metastasis partly by having a negative impact on how the tumor reacts to therapy. For example, tumor cells with limited oxygen supply are less sensitive to radiation therapy and chemotherapy than cells with good oxygen supply. In previous research, breast cancer has an oxygen deficiency in the tumor linked to poorer prognosis and survival. The tissue response to hypoxia is mediated in most cases by a hypoxia-sensitive factor, Hypoxia Inducible Factor-1 (HIF-1). Recently, several publications have shown that even high levels of HIF-1 correlate with poor treatment prognosis in breast cancer and in a 2007 publication, in a study in mice, both tumor development and the formation of metastases were significantly reduced when the malignant tissue lacks HIF -1. In the project for which funding has been applied for, we shall try to define how HIF-1 is important for the formation of metastases in breast cancer.
  • Swedish Research Council
    1 January 2014 - 31 December 2016
  • National Institute of Allergy and Infectious Diseases
    1 August 2012 - 31 July 2017
  • The physiology of hypoxic response
    Wellcome Trust Ltd
    1 August 2011 - 31 December 2018
  • National Institute of Allergy and Infectious Diseases
    5 April 2011 - 31 March 2017
  • National Cancer Institute
    6 January 2011 - 31 December 2015
  • National Institute of Allergy and Infectious Diseases
    2 August 2010 - 31 July 2011
  • Hypoxic response and inflammation: role in breast cancer progression.
    Susan G. Komen Breast Cancer Foundation
    14 August 2008 - 13 February 2012
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