scholarly journals Altered selection on a single self-ligand promotes susceptibility to organ-specific T cell infiltration

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
David E.J. Klawon ◽  
Dana C. Gilmore ◽  
John D. Leonard ◽  
Christine H. Miller ◽  
Jaime L. Chao ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Cell Lineage ◽  
The Body ◽  
Cell Infiltration ◽  
Clonal Deletion ◽  
T Cell Infiltration ◽  
Organ Specific ◽  
T Cell Selection ◽  
Deficient Mice

For the large array of self-peptide/MHC class II (pMHC-II) complexes displayed in the body, it is unclear whether CD4+ T cell tolerance must be imparted for each individual complex or whether pMHC-II–nonspecific bystander mechanisms are sufficient to confer tolerance by acting broadly on T cells reactive to multiple self-pMHC-II ligands. Here, via reconstitution of T cell–deficient mice, we demonstrate that altered T cell selection on a single prostate-specific self-pMHC-II ligand renders recipient mice susceptible to prostate-specific T cell infiltration. Mechanistically, this self-pMHC-II complex is required for directing antigen-specific cells into the Foxp3+ regulatory T cell lineage but does not induce clonal deletion to a measurable extent. Thus, our data demonstrate that polyclonal T reg cells are unable to functionally compensate for a breach in tolerance to a single self-pMHC-II complex in this setting, revealing vulnerabilities in antigen-nonspecific bystander mechanisms of immune tolerance.

scholarly journals Lack of MHC class II molecules favors CD8+T-cell infiltration into tumors associated with an increased control of tumor growth

2017 ◽  
Vol 7 (3) ◽  
pp. e1404213 ◽  
Author(s):  
Nada Chaoul ◽  
Alexandre Tang ◽  
Belinda Desrues ◽  
Marine Oberkampf ◽  
Catherine Fayolle ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Mhc Class Ii ◽  
Cd8 T Cell ◽  
Class Ii ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Mhc Class Ii Molecules

scholarly journals Cancer Cell Intrinsic Expression of MHCII Regulates the Immune Microenvironment and Response to Anti-PD-1 Therapy in Lung Adenocarcinoma

2020 ◽  
Author(s):  
Amber M. Johnson ◽  
Bonnie L. Bullock ◽  
Alexander J. Neuwelt ◽  
Joanna M. Poczobutt ◽  
Rachael E. Kaspar ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Mhc Class Ii ◽  
Cancer Cell ◽  
Multispectral Imaging ◽  
Class Ii ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Mhcii Expression

AbstractMHC class II (MHCII) expression is usually restricted to antigen presenting cells, but can be expressed by cancer cells. We examined the effect of cancer cell-intrinsic MHC class II (csMHCII) expression in lung adenocarcinoma on T cell recruitment to tumors and response to anti-PD-1 therapy. The functional significance of altering csMHCII expression was explored using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis Lung Carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, while LLC tumors are resistant. RNA-seq analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, while resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss- and gain-of-function of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII, and converted tumors from anti-PD-1-sensitive to anti-PD-1-resistant. This was associated with decreased T cell infiltration, lower levels of Th1 cytokines, increased B cell number and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1.

scholarly journals Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001435
Author(s):  
Kohei Shigeta ◽  
Aya Matsui ◽  
Hiroto Kikuchi ◽  
Sebastian Klein ◽  
Emilie Mamessier ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Combination Therapy ◽  
Tumor Vasculature ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Pd1 Blockade ◽  
Endothelial Growth Factor ◽  
Deficient Mice

Background and purposeCombining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic proceduresWe used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findingsRegorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusionsJudicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

scholarly journals GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Robert J. Torphy ◽  
Yi Sun ◽  
Ronggui Lin ◽  
Alayna Caffrey-Carr ◽  
Yuki Fujiwara ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Cell Function ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Deficient Mice

AbstractFor many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.

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