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Longitudinal profiling of tumor specific CD8 T cells using single cell RNA-Seq in mouse lung adenocarcinoma

ABSTRACT: T cell dysfunction is a critical obstacle to productive anti-tumor immunity. Previous work has demonstrated that a subset of dysfunctional CD8+ T cells expresses TCF-1, and that this population sustains the T cell response over time. However, the mechanisms that contribute to the generation and maintenance of TCF-1+ CD8+ T cells remain poorly understood. Here, using a model of lung adenocarcinoma, we demonstrate that TCF-1+ CD8+ T cells are found within both tumor and tumor draining LN (dLN), but phenotypically and functionally differ based on location. In tumors, TCF-1+ CD8+ T cells become dysfunctional with time, are heterogeneous, and decline over the course of progression, while TCF-1+ CD8+ T cells in the dLN remain stable. Blocking egress from the dLN decreased SlamF6+ TCF-1+ CD8+ T cells in tumors, demonstrating that the dLN is a critical reservoir of functional CD8+ T cells. Concomitant with the decline in CD8+ T cells in the tumor, migratory conventional dendritic cell type I (cDC1) numbers decreased in the dLN. Therapeutically, boosting cDC1 numbers and function using Flt3L/anti-CD40 antibody resulted in T cell proliferation within the dLN, an increased SlamF6+ TCF-1+ CD8+ T cells in tumors, and a decreased tumor burden. These data demonstrate the importance of migratory cDC1 cells in boosting TCF-1+ CD8+ T cells in the dLN, and provide rationale for targeting DCs in immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE182028 | GEO | 2021/10/01

REPOSITORIES: GEO

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Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

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Longitudinal profiling of tumor specific CD8 T cells using single cell RNA-Seq in mouse lung adenocarcinoma

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