Periodic Reporting for period 3 - RASImmune (Targeting RAS driven tumour immune evasion)
Reporting period: 2022-08-01 to 2024-01-31
Lung cancer is the most common type of malignant tumour worldwide and the leading cause of cancer-related death, being responsible for some 335,000 deaths per year in Europe. It is caused by genetic damage to the cells lining the lungs by airborne carcinogenic chemicals in the environment, with over 85% of cases being directly attributable to chemicals from tobacco smoke. Several decades of tobacco control measures have resulted in decreasing smoking rates in many countries and this eventually feeds through to reducing rates of lung cancer. However, tobacco usage remains high and rates of smoking-related lung cancer are set to remain a leading cause of death for decades to come.
While work on lung cancer prevention through tobacco control continues, other approaches to reducing the huge health burden of lung cancer include improvements in early diagnosis and improvements in therapy. It is in the latter area that this project is focused. Research over the past forty years has led to a good understanding of the genetic alterations in lung tissue that cause cancer. One gene that is damaged very frequently in lung cancer, and also several other poor prognosis cancers such as those of the colon and pancreas, is known as KRAS. For many years we have been trying to block the function of this gene and we know that doing this can at least temporarily stop the growth of cancers in experimental systems. Drugs that block KRAS have now been developed and approved for clinical use. While they have a significant impact on lung cancer in the short term, unfortunately they seem to only be able to delay progression of the disease temporarily before resistance develops within a few months.
In order to move beyond treatments that only delay advanced cancers for a few months or, at best, years, we need to understand how to eradicate tumour cells completely, not leaving minor populations that go on to develop drug resistance and cause disease relapse. A very interesting area of investigation in this regard is that of immunotherapy. Tumours have to find ways to avoid recognition as foreign by the immune system, and over the past decade drugs known as immune checkpoint inhibitors have been developed that stop the tumour from hiding itself from the immune system. These have achieved remarkable response rates in certain advanced cancers. However, response rates to immunotherapies are highly variable and it is entirely unclear how these therapies can be combined to best effect with other existing treatments. Mechanistic understanding of how immunotherapy can be combined optimally with other therapies is currently lacking and is urgently needed.
In this project, we aim to investigate the interplay between the immune system and the tumour cells in lung cancer, with particular focus on the ways in which the mutated KRAS gene can promote the ability of the cancer to evade immune attack. To allow study of the mechanism by which tumours overcome the immune system locally, we have developed improved mouse models of KRAS driven lung cancers that more closely mimic human tumours, particularly containing high rates of mutations, as are often seen in tobacco smoke induced cancers, which makes the tumours more immunogenic (visible as foreign to the immune system). In particular, we are focusing on how KRAS oncogene driven signaling can supress immune attack on the tumour and how it can co-opt components of the tumour microenvironment to promote tumour cell growth. Key observations are being derived by studying changes in the cell populations present in the tumour microenvironment when KRAS signaling is switched off or on, and what changes occur in gene expression in the various cell types present under these circumstances.
This information is allowing the identification of therapeutic approaches to prevent KRAS mutant lung tumours from hiding from the immune system and we will explore how these might be combined with other existing therapies, particularly those targeting KRAS itself, to enable more effective treatment of this very common and lethal disease, aiming to ultimately achieve complete cures rather than just delay of disease progression.
While work on lung cancer prevention through tobacco control continues, other approaches to reducing the huge health burden of lung cancer include improvements in early diagnosis and improvements in therapy. It is in the latter area that this project is focused. Research over the past forty years has led to a good understanding of the genetic alterations in lung tissue that cause cancer. One gene that is damaged very frequently in lung cancer, and also several other poor prognosis cancers such as those of the colon and pancreas, is known as KRAS. For many years we have been trying to block the function of this gene and we know that doing this can at least temporarily stop the growth of cancers in experimental systems. Drugs that block KRAS have now been developed and approved for clinical use. While they have a significant impact on lung cancer in the short term, unfortunately they seem to only be able to delay progression of the disease temporarily before resistance develops within a few months.
In order to move beyond treatments that only delay advanced cancers for a few months or, at best, years, we need to understand how to eradicate tumour cells completely, not leaving minor populations that go on to develop drug resistance and cause disease relapse. A very interesting area of investigation in this regard is that of immunotherapy. Tumours have to find ways to avoid recognition as foreign by the immune system, and over the past decade drugs known as immune checkpoint inhibitors have been developed that stop the tumour from hiding itself from the immune system. These have achieved remarkable response rates in certain advanced cancers. However, response rates to immunotherapies are highly variable and it is entirely unclear how these therapies can be combined to best effect with other existing treatments. Mechanistic understanding of how immunotherapy can be combined optimally with other therapies is currently lacking and is urgently needed.
In this project, we aim to investigate the interplay between the immune system and the tumour cells in lung cancer, with particular focus on the ways in which the mutated KRAS gene can promote the ability of the cancer to evade immune attack. To allow study of the mechanism by which tumours overcome the immune system locally, we have developed improved mouse models of KRAS driven lung cancers that more closely mimic human tumours, particularly containing high rates of mutations, as are often seen in tobacco smoke induced cancers, which makes the tumours more immunogenic (visible as foreign to the immune system). In particular, we are focusing on how KRAS oncogene driven signaling can supress immune attack on the tumour and how it can co-opt components of the tumour microenvironment to promote tumour cell growth. Key observations are being derived by studying changes in the cell populations present in the tumour microenvironment when KRAS signaling is switched off or on, and what changes occur in gene expression in the various cell types present under these circumstances.
This information is allowing the identification of therapeutic approaches to prevent KRAS mutant lung tumours from hiding from the immune system and we will explore how these might be combined with other existing therapies, particularly those targeting KRAS itself, to enable more effective treatment of this very common and lethal disease, aiming to ultimately achieve complete cures rather than just delay of disease progression.
We have successfully established and characterised new mouse models of cancer that more faithfully represent the human disease because they carry a larger number of mutations in the tumour cells, as is seen in the tumours of human patients who have been long-term tobacco smokers. We have analysed these tumours in detail, focusing on the presence of different types of immune cells in the tumours and how these are altered when the tumours are exposed to drugs inhibiting the function of the KRAS gene, which is commonly mutated in lung cancer.
Using this novel mouse model of lung cancer, have uncovered a novel type of immune response against the tumour. This involves a different part of the immune system to what we normally think of as activated by immune therapy: we see antibodies targeting the tumours, in addition to the T cells, that we already knew can sometimes attack the cancer cells. Antibodies are more typical of the response to viruses like Covid. In both the cancer prone mice and in human patients, we have shown that these are recognising the remnants of ancient fragments of viruses that were incorporated into our DNA hundreds of thousands of years ago, but are now degraded and no longer infectious, so-called endogenous retroviruses.
Using this novel mouse model of lung cancer, have uncovered a novel type of immune response against the tumour. This involves a different part of the immune system to what we normally think of as activated by immune therapy: we see antibodies targeting the tumours, in addition to the T cells, that we already knew can sometimes attack the cancer cells. Antibodies are more typical of the response to viruses like Covid. In both the cancer prone mice and in human patients, we have shown that these are recognising the remnants of ancient fragments of viruses that were incorporated into our DNA hundreds of thousands of years ago, but are now degraded and no longer infectious, so-called endogenous retroviruses.
This work should allow us to identify ways in which to prevent the development of resistance to therapeutic KRAS targeted drugs during lung cancer treatment by engaging the immune system to help destroy tumour cells that have already been weakened by these KRAS drugs. Potentially this could benefit over 50,000 patients a year in Europe that have a specific type of lung cancer, with the KRAS G12C mutation. Our observations about antibody responses against the lung tumours open up the exciting possibility of vaccination based approaches to treated lung cancer, and these will be a major focus of our continuing work on the project.