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CD4 + T-cell help explains clinical benefit of specific intra-tumoral dendritic cell states in human cancer

ABSTRACT: Classical type 1 dendritic cells (cDC1) have a low abundance in the tumor microenvironment (TME), but positively correlate with patient survival. We hypothesized that the ability of cDC1 to relay CD4+ T-cell help for the cytotoxic T lymphocyte (CTL) response explains their clinical benefit. In vitro, contact with activated CD4+ T-cells enabled human cDC1, but no other DC types, to induce a CTL response to cell-associated tumor antigens. Single cell transcriptomics revealed that CD4+ T-cell help uniquely optimized cDC1 and no other DC types in many functions that support antigen cross-presentation and T-cell priming. We robustly identified “helped” cDC1 in a multitude of human cancer types by the overlap in their transcriptomic signature with that of recently defined, positively prognostic tumor-infiltrating DC states. As predicted from the functional effects of CD4+ T-cell help, the transcriptomic signature of “helped” cDC1 correlated with tumor infiltration by CTL and Thelper(h)-1 cells, overall survival and response to PD-1-targeting immunotherapy. These findings reveal a critical role of CD4+ T-cell help delivery via cDC1 to CTL in the TME

ORGANISM(S): Homo sapiens

PROVIDER: GSE218719 | GEO | 2022/12/02

REPOSITORIES: GEO

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Single-cell transcriptomics reveals the role of antigen presentation in liver metastatic breast cancer

Project description:Liver metastasis (LM) is the primary cause of cancer-related mortality in late-stage breast cancer (BC) patients. However, the complexity and diversity of the tumor microenvironment (TME) of LM have not been fully understood. Here we report an in-depth analysis of the transcriptional landscape of liver metastases of 11 patients with secondary hepatic carcinoma at single-cell resolution. Our study reveals that terminally exhausted CD4+ and dysfunctional CD8+ T cells were enriched in metastatic tumor along with low antigen presentation. We also found macrophages were associated with the infiltration profile of CD4+ T cells, while FCN3+ macrophages, type 1 conventional dendritic cells (cDC1) and LAMP3+ DC regulated T cell functions, probably via antigen processing and presentation. MHC expression in FCN3+ macrophage, cDC1 and LAMP3+ DC was reduced in LM compared to those in normal tissues and primary tumor of BC. Dysfunction of antigen presentation in these cells is linked to a worse prognosis in breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC) cohorts and identifies potentially targetable immune inhibitory pathways in secondary hepatic carcinoma. Thus, our results show a cellular diversity of TME in BC-LM, providing valuable insights into the role of tumor infiltrating T cells in liver metastatic cancers.

2024-01-23 | GSE249361 | GEO

Transcriptional basis of CD4 T cel help for memory CD8 T cell formation

Project description:CD4+ T-cell help is required for the generation of CD8+ cytotoxic T lymphocyte (CTL) memory. We here reveal how “help” signals delivered during priming impact memory differentiation of CTLs, as informed by genome-wide analyses. “Help” signals promoted the IL-15-dependent maintenance of central memory (TCM) cells. However, they had a much larger impact on the generation of effector memory (TEM) cells and their gene expression program . CD4+ T-cell help created TEM cells that produced Granzyme B and IFNg after antigen-independent recall with IL-12 and IL-18. Furthermore, “helped” memory CTLs expressed the effector program characteristic of “helped” primary CTLs upon recall with MHC class I-restricted antigen only, due to both epigenetic imprinting and sustained mRNA expression of relevant genes . Thus, CD4+ T-cell help delivered during priming creates CD8+ TEM cells with innate and help-independent recall capacities.

2019-10-23 | GSE135141 | GEO

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.

2016-01-15 | E-GEOD-76889 | biostudies-arrayexpress

RNA-seq of lung myeloid cells from WT and Ptgs2-cKO mice

Project description:To investigate the role of the COX-2-dependent lung fibroblast program in reprogramming lung myeloid cells, we generated fibroblast-targeted Ptgs2 conditional knockout mice by crossing Pdgfra-Cre mice with Ptgs2flox/flox mice. Then we isolated two primary types of lung resident DCs-CD103+ conventional DC (cDC1) and CD11b+ conventional DC (cDC2), and lung monocytes from WT and Ptgs2 cKO mice by fluorescence-activated cell sorting and performed RNA sequencing.

2022-07-19 | E-MTAB-11888 | biostudies-arrayexpress

Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors

Project description:Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remains unclear. We develop a hypermutated model of non-small cell lung cancer, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L+CD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and decreased exhaustion in effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.

2024-03-04 | GSE260743 | GEO

Physical interaction with antigen presenting cells primes a T helper tumor lineage

Project description:Cellular interactions in the tumor microenvironment (TME) drive T cell effector function, or dysfunction, and define a primary mechanism to target anti-tumor T cell immunity. Currently, the interactions that shape T cell function in the TME remain poorly understood. Here, we mapped the molecular programs of T and antigen-presenting cell interactions in human early non-small cell lung carcinoma lesions by physically interacting cell (PIC) sequencing. PIC-seq and imaging identified that in the TME, but not normal lung, PICs are enriched in clonally expanded CD4+PD-1+CXCL13+ T cells, expressing a unique combination of checkpoint molecules, transcription-factors, and cytokines, defining a novel T helper tumor-specific (Tht) program, conserved across cancer types. In vitro and in vivo genetic models of antigen specificity confirmed that the Tht prevalence in TME PICs is driven by tumor-antigen presentation of dendritic cells. Our study highlights CD4+ T-dendritic cell physical interaction as a key factor regulating the TME.

2022-01-11 | GSE160903 | GEO

The molecular basis of CD4 T-cell help for the cytotoxic T-cell response

Project description:CD4+ T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes, resulting from CD4+ T-cell help during priming, as apparent in effector CTLs. This gene expression signature reveals that CD4+ T-cell help optimizes CTLs in the expression of cytotoxic effector molecules, but also in many other functions that ensure optimal efficacy of CTLs throughout their life cycle.

2017-11-07 | GSE89665 | GEO

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

2016-01-15 | GSE76889 | GEO

cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity

Project description:CD4 T cells are thought to help promote anti-tumour responses by ‘licensing’ antigen presenting cells (APCs) that activate CD8 T cells. Conventional type 1 dendritic cells (cDC1s) are responsible for cross-presentation of tumour-derived antigens to CD8 T cells. Prevailing models presume that the cDC1 is licensed by CD4 T cells that are themselves activated by a distinct cDC subset, the cDC2. The recent finding that neoantigens presented by major histocompatibility complex (MHC) class II molecules can promote rejection of tumours that lack MHC class II (MHC-II) surface expression is consistent with an indirect action of CD4 T cells, such as cDC1 licensing. However, no study has directly identified the APC that primes the CD4 T cells responsible for licensing or clearly identified the target of CD4 licensing in vivo. Here, we generated cDC1-specific Cre expressing mouse strain to inactivate or induce expression of MHC-I, MHC-II, or CD40 specifically within the cDC1 lineage. Using a tumour model that relies on CD8 T cells and CD4 T cells for rejection, we discovered that early priming of CD4 T cells against tumour-derived antigens, in contrast to soluble antigens, relied overwhelmingly on the cDC1 and not the cDC2. cDC1 do not simply transport antigen to lymph nodes for processing by cDC2, since lack of MHC-II expression on cDC1 prevented CD4 T cell priming. We also found that CD40 signaling not only affects licensing of cDC1 for CD8 T cell priming, but is also critical for the activation of CD4 T cells. Thus, in the setting of tumour-derived antigens, cDC1 can function as an autonomous platform, capable of priming both CD4 and CD8 T cells and orchestrating their cross-talk required for optimal anti-tumour immunity.

2020-06-11 | GSE152196 | GEO

mRNA expression profile of Lymphocytes by high-throuput sequencing

Project description:The activation of CD4+ T helper (Th) cells is crucial for the induction of cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and re-differentiated the cells into T-lineage cells (iPS-T cells). Although iPS-T cells retained the same T-cell receptor (TCR) as the original Th clone, their gene expression patterns resembled those of group 1 innate lymphoid cells, and CD4 molecule, an essential co-receptor in TCR-mediated Th responses, was not expressed. The transduction of CD4 genes into iPS-T cells enhanced b3a2 peptide–specific responses. iPS-T cells contained a subpopulation that up-regulates CD40 ligand (CD40L) in response to IL-2 and IL-15. Besides CD4 expression, CD40Lhigh iPS-T cells induced antigen-specific DC maturation characterized by enhanced CD83, CD86, and CCR7. In the presence of Wilms tumor 1 (WT1) peptide, DCs conditioned by CD4-modified CD40Lhigh iPS-T cells stimulated the priming of WT1-specific CTLs. These CTLs eliminated WT1 peptide-expressing CML cell lines in vitro and in vivo. Our findings indicate CD4 modification and purification of CD40Lhigh iPS-T cells generates T helper-like cells that induce effective anti-leukemic CTL responses via DC maturation and suggest feasibility of the cells for adoptive immunotherapy against leukemia.

2018-01-31 | GSE94332 | GEO

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