PXD042991

PXD042991 is an original dataset announced via ProteomeXchange.

Title	A multi-target molecule restores immune response in lung cancer through intratumoral CD4+ cytotoxic lymphocytes recruitment
Description	Background: Despite current therapeutic treatments including surgery, chemotherapy, radiotherapy and recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered a dual function of a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the lung cancer immune response. Methods: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterize by flow cytometry. Results In this study, we first show that QAPHA can inhibit HDAC6, leading to upregulation of HSP90, cytochrome C and caspases, found by proteomic analysis. We also confirm that QAPHA induces immunogenic cell death (ICD) by upregulating HMGB1 in vitro and demonstrated its effectiveness as a vaccine in vivo. Remarkably, even at a low concentration (0.5mg/kg), QAPHA achieved complete tumor regression in approximately 60% of intratumorally treated mice, establishing a long-lasting anticancer immune response. Moreover, QAPHA treatment promoted infiltration of neutrophils in the treated mice, reflecting inflammatory cell death promoted. Very interestingly, we show that QAPHA is also able to upregulate MHC-II expression on TC-1 tumor cells in vitro and in vivo. This process participates to the recruitment of CD4+ NKG2D+ CRTAM+ Perforin+ T cells in tumor infiltrate, defined as cytotoxic CD4+ T cells (CD4+ CTL). Finally, we show that tumor regression is strongly correlated to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. Conclusion Collectively, our findings shed light on the discovery of a new multi-target inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate to enhance a specific CD4+ cytotoxic T cell-mediated anti-tumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising therapeutic agent for cancer treatment.
HostingRepository	PRIDE
AnnounceDate	2024-06-16
AnnouncementXML	Submission_2024-06-16_02:08:49.114.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Massimiliano Gaetani
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-14 12:43:20	ID requested
⏵ 1	2024-06-16 02:08:50	announced

10.1136/jitc-2023-007588;

Ducellier S, Demeules M, Letribot B, Gaetani M, Michaudel C, Sokol H, Hamze A, Alami M, Nascimento M, Apcher S, Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells. J Immunother Cancer, 12(4):(2024) [pubmed]

submitter keyword: MoA, Expression proteomics, Mass Spectrometry, CD4 CTL, Drug targets, MHC-II, PISA assay, lung cancer,HDAC6

Massimiliano Gaetani
contact affiliation	Unit of Chemical Proteomics, Division of Chemistry I, Dept. of Medical Biochemistry and Biophysics (MBB), Karolnska Institutet, Biomedicum, Solna, Sweden
contact email	massimiliano.gaetani@ki.se
lab head
Massimiliano Gaetani
contact affiliation	Karolinska Institutet
contact email	massimiliano.gaetani@ki.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD042991
     1. Label: PRIDE project
     2. Name: A multi-target molecule restores immune response in lung cancer through intratumoral CD4+ cytotoxic lymphocytes recruitment