Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment.

NPJ Precision Oncology
Naixue YangXun Lan

Abstract

The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression of immunotherapy prognostic marker genes (IPMGs) in these pathways can predict the patient survival with high accuracy not only in the TCGA cohort (89.36%) but also in two other independent cohorts (80.91%), highlighting that the activity of the IPMGs can reflect the sensitivity of the tumor immune microenvironment (TIME) to immunotherapies. Using mouse models, we show that knockout of one of the IPMGs, MALT1, which is critical for the T-cell receptor signaling, can eliminate the antitumor effect of anti-PD-1 treatment completely by impairing the activation of CD8+ T cells. Notably, knockout of another IPMG, CLEC4D, a C-type lectin receptor that expressed on myeloid cells, also reduced the effect of anti-PD-1 treatment potentially through maintaining the immunosuppressive effects of myeloid cells. Our results suggest that priming TIME via activating the IPMGs may increase the response rate and the effect of immune checkpoint blockers.

References

Mar 22, 1996·Science·D R LeachJ P Allison
Aug 13, 1998·Immunological Reviews·W I WeisK Drickamer
Oct 31, 2002·Nature Immunology·Gavin P DunnRobert D Schreiber
Oct 25, 2003·Science·Astrid A Ruefli-BrasseVishva M Dixit
Aug 17, 2004·Immunity·Gavin P DunnRobert D Schreiber
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
May 4, 2007·The Journal of Clinical Investigation·Jeremy B Swann, Mark J Smyth
Dec 17, 2008·Proceedings of the National Academy of Sciences of the United States of America·David G BrooksMichael B A Oldstone
Aug 26, 2009·Human Gene Therapy·Thomas M SchmittPhilip D Greenberg
Feb 26, 2010·Cold Spring Harbor Perspectives in Biology·Moshe Oren, Varda Rotter
Apr 24, 2010·Nature Reviews. Cancer·Tom D Bunney, Matilda Katan
Dec 23, 2011·Genes & Development·Stephen L ShiaoLisa M Coussens
Feb 7, 2012·Immunology·Fei ZhaoFirouzeh Korangy
May 1, 2012·Nature Biotechnology·Scott L CarterGad Getz
May 12, 2012·CA: a Cancer Journal for Clinicians·John M KirkwoodSoldano Ferrone
Aug 29, 2012·The Journal of Experimental Medicine·Timothy O'SullivanJack D Bui
Jan 18, 2013·BMC Bioinformatics·Sonja HänzelmannJustin Guinney
Aug 16, 2013·Nature·Ludmil B AlexandrovMichael R Stratton
Sep 21, 2013·Nature·Corbin E Meacham, Sean J Morrison
Sep 28, 2014·Bioinformatics·Simon AndersWolfgang Huber
Mar 10, 2015·Nature Methods·Daehwan KimSteven L Salzberg
Apr 4, 2015·Science·Johanna A Joyce, Douglas T Fearon
Sep 12, 2015·Science·Eliezer M Van AllenLevi A Garraway
Sep 18, 2015·Frontiers in Immunology·Huimin YanNoriko M Tsuji
Nov 1, 2015·Science·Eric TranSteven A Rosenberg
Dec 10, 2015·Cancer Discovery·Weiyi PengPatrick Hwu
Sep 17, 2016·Cancer Research·Peiling TsouSamir M Hanash
Mar 24, 2018·Science·Antoni Ribas, Jedd D Wolchok
Apr 10, 2018·Immunity·Vésteinn ThorssonIlya Shmulevich
Jun 27, 2018·Frontiers in Immunology·Rebekka WeberViktor Umansky
Oct 6, 2018·Nucleic Acids Research·Xinxin ZhangYun Xiao

❮ Previous
Next ❯

Citations

Sep 14, 2021·Frontiers in Cell and Developmental Biology·Han ZhaoLan Gong

❮ Previous
Next ❯

Software Mentioned

count
DMwR
VarScan2
ssGSEA
FlowJo
R
htseq
ABSOLUTE
R package
CellMarker

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.