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Conditional deletion of Pdcd1 identifies the cell-intrinsic action of PD-1 on functional CD8 T cell subsets for anti-tumor efficacy

ABSTRACT: PD-1 blockade has a profound effect on the ability of the immune system to eliminate tumors but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) PD-1 KO mice as well as in wild type mice treated with an anti-PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 22-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All 5 subsets expressed granzyme B and secreted IFNγ. Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO and PD-1 Ab treated mice and showed an upregulation of pathways related to CD4 and CD8 T cell activation and enhanced signaling through co-stimulatory molecules and IFNγ. Altogether, using PD-1 cKO we define the intrinsic nature of PD-1 suppression of CD8 T cell responses in tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE171274 | GEO | 2021/12/08

REPOSITORIES: GEO

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

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Conditional deletion of Pdcd1 identifies the cell-intrinsic action of PD-1 on functional CD8 T cell subsets for anti-tumor efficacy

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