ESTRO 2024 - Abstract Book

S5188

Radiobiology - Immuno-radiobiology

ESTRO 2024

2825

Proffered Paper

Impact of JAK inhibitors on anti-tumor immunity after RT combined with immune checkpoint inhibition

Julia Gissibl 1 , Vincent R Timnik 1 , Sarah Diederich 1 , Hannah Felchle 1 , Sophie M Nefzger 1 , Caroline N. Walther 1 , Stephanie E. Combs 1,2,3 , Julius C Fischer 1 1 Technical University of Munich, Department of Radiation Oncology, Munich, Germany. 2 Helmholtz Zentrum München, Institute of Radiation Medicine (IRM), Munich, Germany. 3 German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany

Purpose/Objective:

Janus Kinase Inhibitors (JAKi) are a part of various treatment regimens for hematological, oncological, and autoimmune diseases, and they have shown potential in improving the survival of SARS-CoV-2 patients. Several clinical phase I-II studies are also exploring the potential of JAKi in combination with other targeted cancer therapies (e.g. for the treatment of non-small cell lung carcinoma). JAKi restrain the signaling of over 40 cytokines, including type I interferon (IFN-I). It is known that IFN-I is essential for the induction of anti-tumor immune responses after RT, but continuous IFN-I signaling is also associated with resistance to immune checkpoint inhibitor therapy. Furthermore, tumor cell intrinsic IFN-I signaling may limit anti-tumor immune responses after RT. In sum, preclinical and clinical studies have demonstrated that IFN-I activation can positively or negatively influence the induction of anti-tumor immune responses during radiation therapy (RT), immune checkpoint blockade (ICB), and especially during the combination of both therapies (radioimmunotherapy, RIT). The effects of simultaneous JAKi application in this context are largely not understood.

Material/Methods:

Experimental mouse models (MC38 colorectal carcinoma) were used to analyze the influence of JAKi on IFN-I induction after RT (in vitro) and tumor therapy (in vivo). In vivo: Bilateral tumor models were used to investigate the effects of concurrent JAKi application on the abscopal effect (tumor progression of the abscopal tumor) after RIT (1 x 8 Gy of irradiated index tumor +/- anti-CTLA-4 or anti-PD-1). In addition, the influence of JAKi on established long-term anti-tumor immunity was examined using unilateral tumor models: After tumor induction of a single tumor, mice received 3 x 8 Gy RTx +/- anti-CTLA-4 or anti-PD-1. Three months after this curative therapy, mice were again challenged with the same tumor entity (MC38 tumor cells) to examine the potential of the mice to reject the tumors or delay tumor growth. MC38 tumor rechallenge experiments +/- simultaneous JAKi application were performed to investigate the influence of JAKi on established anti-tumor immunity.

Results:

JAKi inhibit the potential of RT to stimulate systemic anti-tumor immunity in combination with ICB (anti-PD-1 or anti-CTLA-4), resulting in enhanced abscopal tumor growth in both models. Mechanistically, it was found that the timing of JAK inhibition is crucial. While JAKi less severely affect established anti-tumor immunity during rechallenge experiments, simultaneous JAKi therapy during RIT reduces the abscopal tumor regression. Further analysis revealed that JAKi inhibit the tumor cell-intrinsic IFN-I induction after RT of tumor cells, presumably STING dependent.