Immune checkpoint blockade combined with IL-6 and TGF-β inhibition improves the therapeutic outcome of mRNA-based immunotherapy

Lukasz Bialkowski, Kevin Van der Jeught, Sanne Bevers, Patrick Tjok Joe, Dries Renmans, Carlo Heirman, Joeri L Aerts, Kris Thielemans

Onderzoeksoutput: Article

13 Citaten (Scopus)

Samenvatting

Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T-cell exhaustion or disrupt the cross-talk between cancer stem cells and the tumor-promoting microenvironment. Here, we demonstrate that a three-arm combination therapy-consisting of an mRNA-based vaccine to induce antigen-specific T-cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD-1, TIM-3, LAG-3), and antibodies targeting IL-6 and TGF-β-improves the therapeutic outcome in subcutaneous TC-1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor-specific immunity and simultaneously targeting multiple resistance mechanisms.

Originele taal-2English
Pagina's (van-tot)686-698
Aantal pagina's13
TijdschriftInternational Journal of Cancer
Volume143
Nummer van het tijdschrift3
DOI's
StatusPublished - 1 aug 2018

Bibliografische nota

© 2018 UICC.

Vingerafdruk

Duik in de onderzoeksthema's van 'Immune checkpoint blockade combined with IL-6 and TGF-β inhibition improves the therapeutic outcome of mRNA-based immunotherapy'. Samen vormen ze een unieke vingerafdruk.

Citeer dit