PD-1 Mediated Regulation of Unique Activated CD8+ T Cells by NK Cells in the Submandibular Gland
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE281719 | GEO | 2024/12/11
REPOSITORIES: GEO
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T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
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Project description:Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver).
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Project description:Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) due to an overly activated immune system, despite their anti-cancer effects. Here, we observe that ICI treatment is associated with body weight loss in cancer patients. Similarly, anti-PD-L1 exacerbates muscle wasting in cancer cachexia (CAC) mice, despite its tumor suppressive effects, suggesting muscle atrophy as a potential irAE. Notably, CD8+ T cells accumulate in the skeletal muscle of CAC mice, which is amplified by anti-PD-L1. These CD8+ T cells directly promote muscle wasting, but their depletion effectively prevents cachectic features in CAC mice. We identify cathepsin L (CTSL) as an inter-organ target capable of suppressing both cancer and muscle wasting, particularly that driven by CD8+ T cells. Indeed, CTSL blockade effectively mitigates muscle wasting and further enhances the anti-tumor activity of anti-PD-L1. Thus, CTSL represents a dual therapeutic target for both cancer and cachexia, offering the potential to prevent muscle-related irAE when combined with ICIs.
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Project description:Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) due to an overly activated immune system, despite their anti-cancer effects. Here, we observe that ICI treatment is associated with body weight loss in cancer patients. Similarly, anti-PD-L1 exacerbates muscle wasting in cancer cachexia (CAC) mice, despite its tumor suppressive effects, suggesting muscle atrophy as a potential irAE. Notably, CD8+ T cells accumulate in the skeletal muscle of CAC mice, which is amplified by anti-PD-L1. These CD8+ T cells directly promote muscle wasting, but their depletion effectively prevents cachectic features in CAC mice. We identify cathepsin L (CTSL) as an inter-organ target capable of suppressing both cancer and muscle wasting, particularly that driven by CD8+ T cells. Indeed, CTSL blockade effectively mitigates muscle wasting and further enhances the anti-tumor activity of anti-PD-L1. Thus, CTSL represents a dual therapeutic target for both cancer and cachexia, offering the potential to prevent muscle-related irAE when combined with ICIs.
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Project description:Therapeutic antibodies trigger antibody-dependent cellular cytotoxicity (ADCC) of cancer cells and also their antibody-dependent cellular phagocytosis (ADCP) by tumor-associated macrophages (TAMs). We report here our unexpected finding that TAMs that have undergone ADCP of tumor cells induced by therapeutic antibodies display immunosuppressive characteristics and inhibit the proliferation and tumoricidal effects of NK and tumor-specific CD8+ T cells in breast cancers and lymphomas. Mechanistically, we show that DNA released from the phagocytosed tumor cells after ADCP activates caspase 1 inflammasome, leading to IL-1β-mediated PD-L1 and IDO upregulation in these cells. Combined treatment with anti- HER2 antibody and inhibitors of PD-L1 and IDO increased the infiltration of NK and CD8+ T cells and enhanced anti- HER2 therapeutic efficacy in mouse models of HER2+ breast cancers. Furthermore, neo-adjuvant Trastuzumab therapy significantly increased PD-L1 and IDO expression in the TAMs of HER2+ breast cancer patients, which correlate with poor Trastuzumab response and reduced NK and CD8+ T cells in the tumors. Collectively, our findings unveil an unexpected role of ADCP induced by therapeutic antibodies in cancer immunosuppression, and suggest that antibody plus immune checkpoint blockade may provide synergistic therapeutic effects in cancer patients.
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Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>
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Project description:Self-reactive T cells are part of the peripheral T cell repertoire in healthy individuals. Checkpoint receptors like PD-1 allow the establishment of peripheral tolerance by inducing deletion or anergy of self-reactive CD8 T cells, however the high frequency of immune-related Adverse Events (irAEs) among cancer patients receiving checkpoint receptor inhibitor (CPI) immunotherapy led us to question how checkpoint receptors are involved in peripheral T cell tolerance. We developed a novel mouse model for studying peripheral T cell tolerance in the skin where skin-specific expression of T cell antigens (Ags) caused local infiltration of Ag-specific CD8 T cells with effector capacity. In this setting, PD-1 was required for maintaining local tolerance by allowing the co-existence of Ag-expressing cells and Ag-specific effector CD8 T cells in skin without tissue pathology, while CD8 T cell-mediated elimination of Ag-expressing cells and consequent tissue pathology developed in the absence of PD-1-mediated regulation. In this model, PD-1 allowed maintenance of skin tolerance by preventing tissue-infiltrating Ag-specific effector CD8 T cells from 1) acquiring a fully functional, pathogenic differentiation state, 2) secreting significant amounts of effector molecules, and 3) gaining access to Ag-expressing cells in the epidermis. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance where PD-1 allows Ag-specific effector CD8 T cells to persist in a tissue where their cognate Ag is expressed without causing pathology.
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