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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

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

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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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