Dataset Information

Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors

ABSTRACT: We identified certain members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Orally applied, a mix of four Clostridiales strains (CC4) prevented and even successfully treated CRC as a stand-alone therapy.

INSTRUMENT(S): 6550 iFunnel Q-TOF LC/MS

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Michael Scharl

PROVIDER: MSV000087624 | MassIVE | Tue Jun 15 06:29:00 BST 2021

REPOSITORIES: MassIVE

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Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors.

Montalban-Arques Ana A Katkeviciute Egle E Busenhart Philipp P Bircher Anna A Wirbel Jakob J Zeller Georg G Morsy Yasser Y Borsig Lubor L Glaus Garzon Jesus F JF Müller Anne A Arnold Isabelle C IC Artola-Boran Mariela M Krauthammer Michael M Sintsova Anna A Zamboni Nicola N Leventhal Gabriel E GE Berchtold Laura L de Wouters Tomas T Rogler Gerhard G Baebler Katharina K Schwarzfischer Marlene M Hering Larissa L Olivares-Rivas Ivan I Atrott Kirstin K Gottier Claudia C Lang Silvia S Boyman Onur O Fritsch Ralph R Manz Markus G MG Spalinger Marianne R MR Scharl Michael M

Cell host & microbe 20210827 10

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral ...[more]

PMID: 34453895

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Project description:IntroductionChimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since "on-target/off-tumor" cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no "on-target/off-tumor" cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts.MethodsUsing the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity.ResultsSpecific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176- control cells, their response proved to be target-specific.DiscussionGenetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding "on-target/off-tumor" cytotoxicity.