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

En ny serie med kreftmedisiner, såkalte immun sjekkpunkthemmere, virker ved å fjerne en bremse på T-celler, immunsystemets "angrepsceller", noe som forbedrer kroppens naturlige forsvar mot kreft. Disse behandlingene har vist god effekt på flere typer kreft, men dessverre er det en stor andel av pasientene som ikke responderer. I dette prosjektet brukte vi musemodeller av kreft som responderer bedre eller dårligere på immunterapi for å bedre forstå hvorfor noen er motstandsdyktige og for å forbedre terapien for disse krefttypene. Vi fant at andelen av makrofager og andre myeloide immunceller som infiltrerer svulstene varierer mellom modellene som responderer og de som ikke gjør det. Tidligere studier har beskrevet at myeloide celler som makrofager har potensial til å drepe kreftceller, men i mange tilfeller utnyttes av kreftcellene til å dempe immunresponsen til T celler. Vi testet derfor måter å redusere antallet immunhemmende myeloide celler ved å hemme ulike signaler. Overraskende viste det seg at blokkering av et av signalstoffene som var antatt å stimulere disse cellene, hadde motsatt effekt. Svulstene vokste større når det var færre av celletypen monocytter til stede, immunresponsen mot tumoren var svakere, og sjekkpunkthemmerene sluttet å virke. Å tilføre mer av dette signalstoffet i svulsten viste en antitumor effekt hvor kreften vokste saktere. Det ser dermed ut til at dette signalstoffet er nødvendig for å få alarmklokkene til å ringe og sette i gang immunresponsen, på samme måte som når en utløst brannalarm tilkaller brannmenn. Vår studie viser at denne populasjonen av myeloide celler utfører viktige funksjoner, i det minste i tidlige stadiene av kreft hos mus. Videre studier er nødvendige for å undersøke om de samme prosessene foregår i mennesker og for å undersøke om dette eller lignende signaler kan brukes til terapi for å øke antall gunstige myeloide cellene og forbedre responsen på sjekkpunkthemmingsterapi.

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.