The Leukaemia Inhibitory Factor (LIF) interleukin 6 family cytokine is a pleiotropic cytokine involved in several different differentiation processes, among which the induction of hematopoietic differentiation in normal and myeloid leukemia cells and neuronal cell differentiation. It can act as an oncogenic factor, and it also promotes the regulation of cancer associated fibroblasts, radioresistance and chemoresistance. Patients expressing high LIF levels are often experiencing shorter survival (find more here).
It also plays a fundamental role since the very early stages of embryo development, as it generates a local immunosuppressive microenvironment in order to protect the embryo from the mother’s immune system. Its action is needed to afford blastocyst implantation in the uterus.
The role of LIF cytokine in inflammation has been addressed since the early 2000’s, when it was suggested that LIF may act as a mediator of bi-directional cross-talk between neural tissue and the immune system (see here more on Pulmon. Pharmacol. & Ther.)

A new candidate therapy, MSC-1, has now been developed at the Vall d´Hebron Institute of Oncology (VHIO), Barcelona, combining LIF-neutralising antibodies with immunotherapy to promote tumor regression and trigger immune memory. Initial results have been recently published in Nature Communications.

VHIO’s gene Expression & Cancer group directed by Joan Seoane (credit: Katherin Wermke)

According to the study, the new approach may open the way to the identification of new targets for cancer treatment, and MSC-1 represents a possible new first-in-class therapy. “The blockade of LIF in tumors expressing high levels of LIF promotes effector T cell tumor infiltration transforming a T cell excluded tumor into an inflamed tumor”, write the authors, who thinks therapies against LIF may be prove useful for broad applications in cancer treatment. Results indicates that the synergy created with checkpoint inhibitors may be able to induce tumor regression also in very aggressive tumors such as glioblastomas.

A dual mechanism of action to fight cancer

The approach developed by researchers led by Joan Seoane, co-program director of Preclinical and Translational Research at VHIO, and ICREA research professor, is currently undergoing a Phase I clinical trial for safety and efficacy at the Vall d’Hebron University Hospital (HUVH), Memorial Sloan Kettering Cancer Center (New York, USA), and the Princess Margaret Cancer Center (Toronto, Canada).
MSC-1 – a LIF neutralising antibody – acts as a LIF inhibitor able to exert a double mechanism of action. Spanish researchers showed that LIF plays a critical role in the regulation of CD8+ T cell tumor infiltration, and it promotes the presence of protumoral tumor-associated macrophages. Multi-functional cytokine LIF is often highly expressed in tumor cells, where it promotes the proliferation of cancer stem cells. MSC-1 blocks LIF, thus resulting also in a blockade of the tumor-initiating stem cells. More particularly, the pharmacological action causes a decrease of CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages.
The study also showed that combining LIF inhibition with anti-PD1 therapy finally results in the possibility to stop the spreading of metastatic cells and cancer recurrence. “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” observed Monica Pascual-García and Ester Bonfill, co-first authors and post-doctoral fellows of VHIO’s Gene Expression and Cancer Group.

Reactivation of the natural immune response

LIF is an important factor in establishing a crosstalk between the innate and the adaptive immune response: one of the features characteristic of an high LIF expression in tumoral cells is that it causes the block of the natural anti-tumor alarm system and the consequent activation of the immune response. Reactivation of natural immunity may be achieved by LIF inhibition, have now demonstrated researchers. “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” explained Joan Seoane.

Novel agent reactivates an immune call by LIF blockade (credit: Joan Seoane/VHIO)

According to the study, LIF inhibits the CXCL9 gene acting as a signal to immune system T cells. “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“, said Joan Seoane.
The further development of MSC-1 is managed by Mosaic Biomedicals, a VHIO-born spin-off founded by Seoane.