Immune checkpoint blockade (ICB) is a type of immunotherapy approved for lung cancer treatment. Immune checkpoint blockade (ICB) is a class of drugs that can induce CD8 T immune cells to attack tumors.
Unfortunately, only about a fifth of patients with lung cancer benefit from ICB, and long-lasting responses are rare.
Scientists often try to improve the efficiency of ICB by adding other drugs to enhance the CD8 T cells’ effect directly. But, if the tumor has CD8 T cells deficiency, it becomes ineffective.
While looking for ways to improve the power of immunotherapy in lung cancer, scientists at EPFL have investigated a method shown to enhance immunotherapy for other cancers. The group looked at lung cancer models with tumors genetically designed to discover changes in human lung cancer.
In a past study, scientists observed that increasing the numbers of CD8 T cells is possible in mammary tumors by using anti-angiogenic drugs. The drug makes the tumor’s blood vessels more open to CD8 T cells.
The combination of anti-angiogenic drugs with ICB leads to increased recruitment of CD8 T cells to tumors. According to scientists, this fortified army of CD8 T cells is better able to fight the tumor.
This approach seems to improve the treatment of certain other cancer types, such as liver cancer. However, it was found ineffective in the lung cancer models. In contrast, it causes some lung tumors to grow faster.
Amaia Martinez-Usatorre, a lead author on the study and a postdoc in Professor Michele De Palma’s lab, said, “This was an apparent paradox… and a setback.”
Further study revealed the possible culprit for this. Scientists found that the anti-angiogenic drug prompts another type of T cell, called regulatory T cells, or Tregs. In healthy organs, these two types of T cells work in concert, with CD8 T cells helping to clear infected cells and Tregs safeguarding tissue to prevent damage that could occur in the long term.
Ece Kadioglu, a Ph.D. student in the De Palma lab and study co-author, said, “This was bad news because Tregs are known to be immunosuppressive, meaning that they can thwart the immune response by CD8 T cells against cancer. The ICB could not distinguish between ‘good’ CD8 T cells and ‘bad’ Tregs. It was empowering both. More Tregs mean more immunosuppressive effect, facilitating tumor growth.”
Scientists addressed this problem by identifying vulnerabilities in the Tregs. They found that the Tregs in tumors depend on macrophages for their survival. Along with helping the Tregs to thrive, the macrophages also support cancer growth in several ways.
Martinez-Usatorre said, “When we analyzed human lung cancer datasets, we found that the more macrophages, the more Tregs there were in the lung tumors. This confirmed that we were likely onto something, that what we saw in the experimental tumor models was relevant to human disease. Macrophages and Tregs establish a dangerous liaison in lung cancer. To enhance the efficacy of ICB, we’d need to break up this liaison.”
In particular, scientists found two types of macrophages in lung tumors. Scientists profiled them to identify molecules to target them pharmacologically.
One type of tumor-associated macrophage expressed the protein CSF1R and needed it to survive. Hence, scientists used an antibody to block CSF1R and eliminated it from the tumors. However, this trick was not achievable in the second type as it did not express CSF1R and was not dependent on it. Also, it was sensitive to a form of chemotherapy called cisplatin.
This two-front attack combining cisplatin and the CSF1R antibody eliminated both macrophage types and left few macrophages in the tumors. In turn, the Tregs were also destroyed because now they lacked vital macrophage support.
Elimination of both macrophages and Tregs left only the ‘good’ CD8 T cells in tumors. With the increased number of CD8 T cells unhindered by Tregs, the ICB action was unleashed against the tumors, providing remarkable benefits.
Martinez-Usatorre said, “We were able to induce the regression of about 70% of the tumors. For comparison, only 15-20% of human lung cancer tumors currently respond to ICB. So it would be dramatic if this strategy could be translated to patients.”
Professor Michele De Palma said, “This combination is promising. That’s a real achievement for this study. We are currently in discussions to bring it forward to clinical trials. And as the drugs – cisplatin and the CSF1R antibody – are approved treatments for certain human diseases, this could expedite clinical testing of the strategy.”
- A. Martinez-Usatorre, E. Kadioglu et al. Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci. Transl. Med. 13, eabd1616 (2021). DOI: 10.1126/scitranslmed.abd1616