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FRIPRO-Fri prosjektstøtte

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

Alternative title: PD-1-blokkerende immunterapier mot kreft - uoppdagede muligheter for øket effekt gjennom aktivering av tumor-assosierte makrofager (TAM)

Awarded: NOK 3.5 mill.

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. In this project, we used mouse models of cancers that respond better or worse to immunotherapy to better understand why some are resistant and to improve the therapy for those types of cancer. We found that the frequency of macrophages and myeloid immune cells that infiltrate the tumors, vary between the ones that respond and those that do not. Previous studies have described that these cells have the potential to help kill cancer cells but are in many cases used by the cancer cells to dampen the anti-tumor immune response. We therefore tested ways of reducing the number of such suppressive myeloid cells by targeting various pathways. Surprisingly, blocking one of the signaling molecules previously thought to increase these cells showed the opposite effect. The tumors grew bigger when there were less of the cell type monocytes present, the anti-tumor immune response was weaker and checkpoint inhibition therapy stopped working. Providing more of this signal molecule in the tumor showed an anti-tumor effect with less tumor growth. It thus appears that this signaling molecule is required for ringing the alarm bell and mounting the first response to the tumor, much like fire fighters called to a fire by the hit of a button. This study shows that this population of myeloid cells perform important functions, at least during the early stages of cancer in mice. Further studies are needed to translate this to human disease and to investigate if this or similar signals can be used for therapy to increase the beneficial myeloid cells and improve response to checkpoint inhibition therapy.

This project has produced research findings that elucidate a previously unappreciated role of a specific signaling protein in inducing beneficial myeloid immune responses to cancer, and not just cells with suppressive functions. Contrary to previous studies, targeting this signaling did not. This will contribute to a better understanding of the early immune responses to cancer and the beneficial roles of such alarmins. It opens the way to explore the use of similar signals as an additional boost to checkpoint inhibition, and a possible way to combat resistance to CPI treatment. Outcomes from this project includes high level training in methods for quantitative and qualitative analysis of immune responses, as well as scientific discourse and communication. It has also provided the basis for a continued collaboration and exchange between Kyoto University and Oslo University Hospital, and academic career development for the project manager with increased experience in independent research.

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.

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FRIPRO-Fri prosjektstøtte

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