Targeting Tumor-associated macrophages (TAM) to increase the efficacy of PD-1 blockade cancer immunotherapy

A new range of cancer immunotherapy, the immune checkpoint inhibitors, works by removing a break on T cells, the “attack cells” of the immune system, which improves the body’s natural defense against cancer cells. These therapies have shown great responses in various types of cancer, but unfortunately there is a large fraction of patients who do not respond. T cells and other “attack cells” of the immune system are constantly kept in check and regulated by signal compounds that increase or reduce the activity of the cells, as well as determining what type of response should be produced. Putting together just the right “soup” of signal compounds can be very complex, and one of the “master chefs” for this job is the macrophage. Macrophages are immune cells which receive many different signals from the environment in the tissues and respond to these by sending out the appropriate signal compounds in return. Unfortunately, cancer cells may play tricks on the macrophages to make them reduce the immune response targeted at eliminating cancer. This can result in macrophages “helping” cancer cells in escaping the T cell attack and cause macrophages to involuntarily helping the cancer cells survive, and even fail to respond to checkpoint inhibitors. The signals that guide the functions of macrophages are very intricate, and a lot of work remains to understand these signals when they are combined together in an organism with cancer. In this project, we are investigating the effect of blocking various signals in mouse models of cancer. Furthermore, we are working to investigate how such a blockade would influence the immune cells when combined with checkpoint inhibitors. We want to better understand which signals we should block or increase to strengthen the immune response against cancer. Our future goal is to develop immunotherapies that, when combined with checkpoint inhibitors, can result in antitumor response in a bigger group of the patients.

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Decades of research and vast attempts at stimulating protective immune responses against cancer were largely unsuccessful until the recent discovery of immune checkpoints. Drugs which block these “brakes on the immune system”, first described by Prof. Honjo with PD-1 and Prof. Allison with CTLA-4, have initiated a revolution in the field of cancer immunotherapy and made a significant impact on patient survival. However, despite great promise and therapeutic benefit in previously fatal cancers, it is becoming clear that checkpoint blockade is characterized by lack of response in a significant portion of patients. The lack of understanding of the resistance mechanisms to checkpoint inhibitors or successful markers predicting response, pose a great therapeutic and societal problem, as these therapies are still very expensive. Tumor-associated macrophages (TAMs) play key roles in the generation and regulation of anti-tumor T cell responses, as well as mediating many other effects in tumor development. In addition, TAMs have been shown to express the PD-1 ligand 1 and 2, and may therefore play key roles in PD-1-mediated immune suppression. The study of these cells has therefore been recognized as highly important for improving the clinical efficacy of PD-1 signaling blockade. However, the effect of checkpoint inhibitors on TAMs is not yet well understood. This project will explore how PD-1 signal blockade alter the phenotype and function of TAMs, both in responding and non-responding tumors. We aim to explore whether metabolic alterations and mitochondrial activation, as have been described in T cells, also occurs in TAMs and whether further metabolic targeting can improve TAM antitumor function. Our main goal is to better understand whether differences in TAM phenotype may explain some of the observed resistance to checkpoint inhibition, and to contribute to the development of new strategies to improve the cross-talk between T cells and TAMs.