TY - JOUR
T1 - Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers
AU - Mugarza, Edurne
AU - van Maldegem, Febe
AU - Boumelha, Jesse
AU - Moore, Christopher
AU - Rana, Sareena
AU - Llorian Sopena, Miriam
AU - East, Philip
AU - Ambler, Rachel
AU - Anastasiou, Panayiotis
AU - Romero-Clavijo, Pablo
AU - Valand, Karishma
AU - Cole, Megan
AU - Molina-Arcas, Miriam
AU - Downward, Julian
N1 - Funding Information: We thank the science technology platforms at the Francis Crick Institute including the Biological Research Facility, Advanced Sequencing Facility, Computational Biology, Genomics Equipment Park, Experimental Histopathology, FACS, and Cell Services. We thank P. Hobson and D. Levi for assistance with imaging mass cytometry. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001070), the UK Medical Research Council (FC001070), and the Wellcome Trust (FC001070), and by funding to J.D. from the European Research Council Advanced Grant RASIMMUNE and a Wellcome Trust Senior Investigator Award 103799/Z/14/Z. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved
PY - 2022/7/22
Y1 - 2022/7/22
N2 - Recently developed KRASG12C inhibitory drugs are beneficial to lung cancer patients harboring KRASG12C mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRASG12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition up-regulates interferon signaling via Myc inhibition, leading to reduced tumor infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRASG12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs.
AB - Recently developed KRASG12C inhibitory drugs are beneficial to lung cancer patients harboring KRASG12C mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRASG12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRASG12C inhibition up-regulates interferon signaling via Myc inhibition, leading to reduced tumor infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRASG12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRASG12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRASG12C inhibitors with anti-PD1 drugs.
UR - http://www.scopus.com/inward/record.url?scp=85134764791&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciadv.abm8780
DO - https://doi.org/10.1126/sciadv.abm8780
M3 - Article
C2 - 35857848
SN - 2375-2548
VL - 8
SP - eabm8780
JO - Science advances
JF - Science advances
IS - 29
M1 - eabm8780
ER -