Results from a study spearhead by researchers at the Vall d´Hebron Institute of Oncology (VHIO), show that the blockade of the multi-functional cytokine LIF induces tumor-infiltrating T Cells to hone in on and eliminate cancer. Reported today in Nature Communications, this research was led by corresponding and co-first author Joan Seoane, Co-Program Director of Preclinical and Translational Research at VHIO, and ICREA Research Professor, and has now culminated in a Phase I clinical trial currently assessing the safety and efficacy of LIF inhibitors in patients across three sites: the Vall d'Hebron University Hospital (HUVH), Memorial Sloan Kettering Cancer Center (MSKCC - New York, USA), and the Princess Margaret Cancer Center (Toronto, Canada).
Developed by VHIO, novel agent MSC-1 inhibits LIF and has now been shown to have a dual mechanism of action. First, in tumors expressing high levels of LIF, this protein promotes the proliferation of cancer stem cells. LIF blockade eliminates these tumor-initiating stem cells, putting the brakes on metastatic cell spread and cancer recurrence.
Additionally, elevated LIF expression disables the anti-tumor alarm system and stops the immune system from thwarting cancer's plans. Blocking LIF reactivates the alarm to call an anti-tumoral immune response.
Pioneer of previous LIF studies, Joan Seoane and his team were the first to establish a link between this multi-functional protein and cancer as well as show that LIF blockade eliminates cancer stem cells and prevents disease progression and recurrence. In this present paper, they have now revealed its implication in the immune system's anti-cancer response.
When foreign bodies or alterations in healthy cells are detected, a biological alarm alerts the immune system to act against these 'dealers' of damage. "We have discovered that LIF silences this alarm which enables cancer to dodge the immune system's innate response. It´s just like a bank robber deactivating an alarm to escape detection by the police," explains Joan Seoane.
More specifically, the researchers have shown that LIF inhibits the CXCL9 gene, which acts as a signal to lure immune system T cells. LIF blockade induces these immune system soldiers to invade, attack and destroy tumors. "We have observed that LIF inhibition in tumors expressing high levels of this protein reactivates the signal to T cells to target and destroy cancer," says Joan.
This study also shows that combining LIF inhibition with anti-PD1 therapy powerful blows against cancer.
Once the T cells infiltrate the tumors, they are activated by anti-PD1 immunotherapy. In animal models the pairing of both agents not only halted tumor growth but also, in some cases, made tumors disappear. In these cases, the immune memory is activated and the system 'remembers' the tumor and that particular does not reappear even when more tumor cells emerge."
Monica Pascual-García and Ester Bonfill, co-first authors and Post-Doctoral Fellows of VHIO's Gene Expression and Cancer Group directed by Joan
After several years' research and validating LIF's promise as a therapeutic target in preclinical and experimental models, Joan founded Mosaic Biomedicals, a VHIO-born spin-off that launched to identify, develop, potentiate and translate novel therapies into benefits for patients at the bedside as quickly as possible. Mosaic has since brought the first-in-class MSC-1 LIF inhibitor closer to the clinic. This promising agent is currently being assessed in clinical trials for further development.
Manipulating Mother Nature's love for LIF
LIF protects cancer in the same way a mother protects her embryo. Throughout evolution LIF has emerged as a solver of a serious issue among mammals: the fact that a living being exists inside another. The embryo has antigens from the father, so why then, is it not rejected by the mother's immune system? LIF protects the embryo and induces the proliferation of embryonic stem cells, resulting in its 'safe' development.
This present study exposes the parallels between embryogenesis and cancer. Joan's team have now shown that LIF assumes a crucial role in embryogenesis by protecting the embryo from the mother's immune system.
Cancer seizes on this molecular mechanism induced by LIF and uses it for its own gain. LIF is aberrantly expressed in some tumors when it shouldn't be, and shields tumors from the patient's own immune system; in the same way that it protects the embryo. Similarly, instead of embryonic stem cells, found in cancer, LIF promotes the proliferation of tumor stem cells.
This new therapeutic window is not open to all tumor types. It only shows promise for the treatment of tumors expressing high levels of LIF. The preselection of patients identified with high LIF levels detected in their tumors is critical in more precisely matching this novel therapy to those patients who would be most likely to benefit.
"Tumor types with typically high LIF levels include glioblastoma, pancreatic, ovarian, lung, and prostate cancers. Importantly, we have also observed that these cancers are also more aggressive and indicative of a poor prognosis," adds Joan.
He concludes, "These findings are the fruit of a major body of work, mainly fueled by the Spanish Association against Cancer (AECC) and the European Research Council (ERC). We are equally grateful to the FERO Foundation, and the BBVA Foundation's Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI), for their backing and belief in this research project."
Vall d'Hebron Institute of Oncology
Pascual-García, M. et al. (2019) LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nature Communications. doi.org/10.1038/s41467-019-10369-9.