MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Targeted therapy represents one of the most important approaches in modern cancer therapy. The basic idea is to identify specific mutations that are responsible for cancer growth and to attack them with drugs. Today, for example, many lung, breast cancer and melanoma patients can be treated in a targeted manner. However, many patients develop resistance to the personalized drugs in the course of treatment, so that the tumors start to grow again.Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients.

Research team led by Martin Sos (Institute of Pathology, Department of Translational Genomics and Center for Molecular Medicine Cologne at the Faculty of Medicine and the University Hospital Cologne report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment.

In their study the researchers uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage.

Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. The study is published in the renowned scientific journal Nature Communication (Sept. 17, 2021 - DOI: 10.1038/s41467-021-25728-8 .

"We were able to show that cancer cells, instead of dying, can also enter an inactive dormant state in response to targeted cancer therapies. We assume that some of the cancer cells in this state survive the therapy, and can later lead to a relapse of the patient," explains Johannes Brägelmann, first author of the study and junior research group leader at the Mildred Scheel School of Oncology Cologne at the University Hospital of Cologne, who was recently awarded with the Career Advancement Program Funding of the Center for Molecular Medicine Cologne.

"Our analyses now show that this dormant state during targeted therapy is also accompanied by a cellular stress response leading to an activation of the innate immune system of the cancer cells. The dormant cancer cells thus become more visible to the body's own immune system and can be targeted and killed. Unfortunately, this inflammatory response in the tumor cells, triggered by the targeted cancer therapy, is not sufficient to trigger such a strong immune response of the body that all cancer cells are killed" explains Carina Lorenz, co-first author of the paper.

Therefore, the researchers analyzed the immune response in more detailed in collaboration with cooperation national and international partners and then tested the potential therapeutic approaches to further increase the therapy in a targeted manner. In their studies the researchers were able to show that cancer cells in a "dormant state" can be killed particularly well by combining them with so-called RIG-I agonists. RIG-I is an intracellular receptor of the innate immune system, which actually serves to recognize foreign nucleic acids if, for example, a virus has invaded a cell. The RIG-I agonists can be used particularly well against cells in a sleeping state, since cells in this state react particularly sensitively to this type of direct immune response.

"In summary, instead of dying, tumor cells can also enter an inactive state in response to targeted cancer therapies, which allows them to survive the therapy, but creates new targets. By molecularly analyzing this state, we have developed a new therapeutic approach in which we combine targeted anticancer drugs with appropriate immunotherapy to improve the therapeutic response. Future clinical trials will have to clarify to what extent these new combination therapies can improve the survival of individual patient groups", Martin Sos summarizes the result of the study.

The study was funded by the German Federal Ministry of Education and Research (BMBF), German Cancer Aid and the Center for Molecular Medicine Cologne among others.

Original paper:
Brägelmann J#, Lorenz C#, Borchmann S, Nishii K, Wegner J, Meder L, Ostendorp J, Ast DF, Heimsoeth A, Nakasuka T, Hirabae A, Okawa S, Dammert MA, Plenker D, Klein S, Lohneis P, Gu J, Godfrey LK, Forster J, Trajkovic-Arsic M, Zillinger T, Haarmann M, Quaas A, Lennartz S, Schmiel M, D'Rozario J, Thomas ES, Li H, Schmitt CA, George J, Thomas RK, von Karstedt S, Hartmann G, Büttner R, Ullrich RT, Siveke JT, Ohashi K, Schlee M, Sos ML.
MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I
Nat Commun. 2021 Sep 17;12(1):5505. DOI: 10.1038/s41467-021-25728-8 . PMID: 34535668
# Contributed equally.