Posted March 9, 2020
Amer A. Beg, Ph.D., H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Mengyu Xie, Ph.D., H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

The increase in Food and Drug Administration (FDA)-approved immunotherapies for lung cancer over the past 5 years has opened a promising new avenue for treatment in many patients, and in select subsets of lung cancer patients, these treatments have been very successful in improving outcomes. In general, however, immunotherapies only work in very specific variants of the disease, so a primary focus of immunotherapy bench research is to increase the response to treatment.

Dr. Amer Beg, at the Moffitt Cancer Center, is focused on methods that can increase immune surveillance within tumors and therefore, increase the likelihood of response to an immune-stimulating treatment. Immune surveillance refers to the ability of an individual’s immune system to access a tumor, identify it as “foreign,” and destroy tumor cells. This function is commonly repressed in lung cancer tumors; however, increased immunotherapy effectiveness is often associated with patients who have a more active immune surveillance response. With funding from a Fiscal Year 2014 Established Investigator - Idea Development Award, Dr. Beg investigated the roles of specific oncogenic mutations in the suppression of the immune surveillance response and tested methods to overcome this suppression, leading to increased response to immunotherapy.

Dr. Beg’s study builds off the prior discovery that MEK inhibitors (MEKi), which have been used to limit the uncontrolled growth of cancer cells, increase the number of T cells that are able to infiltrate the tumor, improving immune surveillance. While investigating the molecular pathways involved in MEK inhibition, Dr. Beg and his team found that there is cross-talk between MEKi and cytokine signaling pathways that play a key role in triggering immune response and inflammation. Treatment with MEKi and TNFα + IFNγ significantly increased cell growth arrest and induction of cell death via apoptosis. A key underlying mechanism discovered in this study was the ability of MEKi to increase cell surface expression of TNFa receptor 1 (TNFR1).

Dr. Beg’s team then compared the effect of MEKi in combination with cytokines TNFα and IFNγ or immune checkpoint inhibitors (e.g., PD-1 antibodies). The findings of these experiments demonstrated that the combined treatment (in both cases) is the most effective at reducing tumor size. However, the combination of MEKi and PD-1 antibody had the most dramatic impact on tumor growth. These results suggest that combining MEKi with agents that promote TNFα and IFNγ expression, such as checkpoint blockade or T cell adoptive cell therapy (ACT), may help achieve greater benefit in lung cancer patients than MEKi alone, or MEKi in combination with direct systemic administration of TNFα and /or IFNγ, which is expected to be highly toxic.

These results show significant promise for those patients hoping to have access to immunotherapies, but who may have not responded well to immunotherapy alone. By combining two FDA approved therapies, it may be possible to improve patient outcomes and to translate these results to the clinic in a much shorter timeline than completely new therapies. Dr. Beg is continuing to extend upon this idea of combination therapies to improve response to immunotherapy and has moved on to clinical trials to test the safety and efficacy of similar combination treatments. 

MEK inhibitors (MEKi) lead to inhibition of downstream ERK kinases to increase cell surface expression of TNFR1 through a presently unclear mechanism (step 1 in figure). This in turn activates the NF-kB transcription factor (p50+RelA complex) and potentially other TNFR1 regulated transcription factors such as AP1 (step 2 in figure). Combined action of NF-kB, AP1 and IFNg induced STAT1 transcription factor leads to increased expression of immune surveillance genes. The increase in TNF expression establishes a positive feedback signaling loop with TNFR1 to augment signaling. Enhanced signaling from TNFR1 significantly increases cell death via apoptosis (step 3 in figure).

Publication:

Xie M, Zheng H, Madan-Lala R, et al. 2019. MEK Inhibition Modulates Cytokine Response to Mediate Therapeutic Efficacy in Lung Cancer. Cancer Res. 79(22):5812-5825. Epub 2019 Jul 30. PMID: 31362929. Published.

Link:

Public and Technical Abstracts: Impact of Inhibition of KRAS/STK11-Induced Immune Suppression in Enhancing Immunotherapy Response

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