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Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

ABSTRACT: Signals emanating from the T cell receptor (TCR), co-stimulatory receptors, and cytokine receptors each influence CD8 T cell fate. Understanding how these signals respond to homeostatic and microenvironmental cues can reveal new ways to therapeutically direct T cell function. Through forward genetic screening in mice, we discover that loss-of-function mutations in LDL receptor related protein 10 (Lrp10) causes naïve and central memory CD8 T cells to accumulate in peripheral lymphoid organs. Lrp10 encodes a conserved cell surface protein of unknown immunological function. T cell activation induces Lrp10 expression, which post-translationally suppresses IL7 receptor (IL7R) levels. Accordingly, Lrp10 deletion enhances T cell homeostatic expansion through IL7R signaling. Lrp10-deficient mice are also intrinsically resistant to syngeneic tumors. This phenotype depends on dense tumor infiltration of CD8 T cells, which display increased memory cell characteristics, reduced terminal exhaustion, and augmented responses to immune checkpoint inhibition. Here, we present Lrp10 as a new negative regulator of CD8 T cell homeostasis and a host factor that controls tumor resistance with implications for immunotherapy.

SUBMITTER: Dr. Evan Nair-Gill

PROVIDER: S-SCDT-10_1038-S44319-024-00191-W | biostudies-other |

REPOSITORIES: biostudies-other

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Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity

Project description:Through forward genetic screening, we found a gene called LDL receptor Related Protein 10 (Lrp10) that plays an important role in the homeostasis and differentiation of peripheral CD8 T cells through its effects on the interleukin 7 receptor (IL7R). Lrp10 knockout mice exhibit enhanced resistance to MC38 tumor growth, and we sought to better define the tumor infiltrating Lrp10+/+ and Lrp10-/- CD8T cells using single cell RNA seq and paired single cell TCR sequencing.

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Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity

Project description:Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity

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Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2).

Project description:Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment(TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGF? and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2-PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGF?-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.

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Autophagy Suppresses CD8+ T cell Anti-tumour Immunity

Project description:Here we demonstrate that inactivation of the essential autophagy genes, Atg5, Atg14, or Atg16L1 results in tumour rejection. Despite a significant reduction in the total number of CD8+ tumour infiltrating lymphocytes (TILs), loss of Atg5 causes a profound shift toward IFNg and TNF producing effector memory cells. Consistent with this, adoptive transfer with Atg5-/- T cells promotes tumour control. Mechanistically, CD8+ T cells lacking autophagy exhibit enhanced glucose metabolism resulting in global changes in histone trimethylation and increased transcriptional activation of effector target genes. Restricting glucose is sufficient to suppress autophagy-dependent increases in effector function and reverse alterations in histone trimethylation. These findings identify autophagy as a cell-autonomous negative regulator of CD8+ T cell anti-tumour immunity with implications on T cell-based immunotherapy.

2019-04-09 | GSE117757 | GEO

A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity.

Project description:The cell-intrinsic mechanisms guiding naive CD8+ T cells for clonal expansion and memory generation via homeostatic proliferation (HP) are unclear. Here, we have shown that HP of naive CD8+ T cells requires IL-7-, but not IL-15-induced mTOR kinase activation. HP-induced mTOR enhances transcription factor T-bet for functional maturation and CD122 expression, which sensitizes for an IL-15-dependent memory transition by favoring transcription factor Eomesodermin over T-bet. Inhibition of mTOR blocks T-bet and CD122 expression but preserves memory in an IL-15-independent manner by promoting Eomesodermin expression. The ability of rapamycin to augment HP-induced memory was cell-intrinsic given that silencing mTOR in CD8+ T cells generated identical outcomes. Strikingly, HP-induced CD8+ T cell memory generated by IL-15-dependent or -independent mechanisms demonstrated identical tumor efficacy. These results indicate a central role for mTOR in HP-induced CD8+ T cell responses and demonstrate the importance for CD8+ memory in HP-induced tumor efficacy.

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PRMT1 suppresses anti-tumor immunity

Project description:PRMT1 is known as a regulator of immune function by directly interacting with interferon receptors, methylating STAT1, and promoting B cell and macrophage differentiation by methylating CDK4 or B cell antigen receptor However, the function of PRMT1 as a therapeutic target of cancer remains largely elusive, particularly for its role in cancer immunosurveillance. Here, we performed bulk RNA-seq for CT26, a mouse tumor cell line, after either knocking down of endogeneous Prmt1 or blocking PRMT1 by two specific inhibitors, namely MS023 and GSK3368715.

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PRMT1 suppresses anti-tumor immunity

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Localized expression of GITR-L in the tumor microenvironment promotes CD8+ T cell dependent anti-tumor immunity.

Project description:The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR) protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L) in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined, the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited a similar delay in tumor growth. The localized expression of GITR-L on tumor cells led to a significant increase in CD8+ T cell infiltration compared to the levels seen in control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth.

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PI3K?/? inhibition promotes anti-tumor immunity through direct enhancement of effector CD8+ T-cell activity.

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