Impact of Chemical-Induced Mutational Load Increase on Immune Checkpoint Therapy in Poorly Responsive Murine Tumors

Molecular Cancer Therapeutics
Elizabeth A KuczynskiR S Kerbel

Abstract

A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although t...Continue Reading

References

Jan 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·T Boon, O Kellermann
Oct 1, 1979·Proceedings of the National Academy of Sciences of the United States of America·A Van PelT Boon
Jan 1, 1991·Methods in Enzymology·P L Foster
Mar 22, 1996·Science·D R LeachJ P Allison
Jan 12, 2011·Annual Review of Immunology·Matthew D VeselyMark J Smyth
Jan 25, 2011·Nature Reviews. Cancer·Giulio FranciaRobert S Kerbel
Mar 23, 2012·Nature Reviews. Cancer·Drew M Pardoll
May 15, 2012·Bioinformatics·Christopher T SaundersR Keira Cheetham
Feb 12, 2013·Nature Biotechnology·Kristian CibulskisGad Getz
Aug 16, 2013·Nature·Ludmil B AlexandrovMichael R Stratton
Nov 20, 2014·The New England Journal of Medicine·Alexandra SnyderTimothy A Chan
Nov 28, 2014·Nature·Matthew M GubinRobert D Schreiber
Dec 9, 2014·The New England Journal of Medicine·Stephen M AnsellPhilippe Armand
Apr 4, 2015·Science·Ton N Schumacher, Robert D Schreiber
May 8, 2015·Nature Medicine·Stephen E GouldFrederic J de Sauvage
Jun 2, 2015·The New England Journal of Medicine·Dung T LeLuis A Diaz
Jun 2, 2015·The New England Journal of Medicine·Julie BrahmerDavid R Spigel
Sep 12, 2015·Science·Eliezer M Van AllenLevi A Garraway
Oct 10, 2015·Science·Matthew M Gubin, Robert D Schreiber
Mar 24, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Eric BouffetUri Tabori
Apr 16, 2016·Nature Reviews. Cancer·Suzanne L TopalianDrew M Pardoll
Apr 17, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Priti S HegdeStefan Evers
May 11, 2016·Genome Biology·Bernadett SzikrisztDávid Szüts
Nov 3, 2016·Cancer Immunology Research·Douglas B JohnsonChristine M Lovly
Oct 21, 2016·Cell Reports·Marios GiannakisLevi A Garraway
Dec 3, 2016·The Journal of Experimental Medicine·Antoni Ribas, Siwen Hu-Lieskovan
Dec 8, 2016·Cancer Immunology Research·Suzanne I S MoselyRobert W Wilkinson
Jan 20, 2017·Cell Communication and Signaling : CCS·Richard GreilLisa Pleyer

❮ Previous
Next ❯

Citations

May 21, 2020·British Journal of Haematology·Nicole A CarreauCatherine Diefenbach
Jan 13, 2019·Journal of Experimental & Clinical Cancer Research : CR·Elaine Reguera-NuñezRobert S Kerbel
Oct 30, 2019·Journal of Experimental & Clinical Cancer Research : CR·Crescenzo D'AlterioStefania Scala
Jul 29, 2020·The Oncologist·Nicole A CarreauCatherine Diefenbach
Nov 30, 2018·Chemical Reviews·Bernhard EnglingerWalter Berger
Dec 11, 2021·Science Advances·Zhuoya WanSong Li

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Acute viral rhinopharyngitis

Acute viral rhinopharyngitis, also known as "common cold", is an acute, self-limiting viral infection of the upper respiratory tract involving the nose, sinuses, pharynx and larynx. Discover the latest research on acute viral rhinopharyngitis here.