ALBERT

Description: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Twyman-Saint Victor, Christina -- Rech, Andrew J -- Maity, Amit -- Rengan, Ramesh -- Pauken, Kristen E -- Stelekati, Erietta -- Benci, Joseph L -- Xu, Bihui -- Dada, Hannah -- Odorizzi, Pamela M -- Herati, Ramin S -- Mansfield, Kathleen D -- Patsch, Dana -- Amaravadi, Ravi K -- Schuchter, Lynn M -- Ishwaran, Hemant -- Mick, Rosemarie -- Pryma, Daniel A -- Xu, Xiaowei -- Feldman, Michael D -- Gangadhar, Tara C -- Hahn, Stephen M -- Wherry, E John -- Vonderheide, Robert H -- Minn, Andy J -- KL2TR000139/TR/NCATS NIH HHS/ -- P01AI112521/AI/NIAID NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA016520/CA/NCI NIH HHS/ -- P50 CA174523/CA/NCI NIH HHS/ -- P50CA174523/CA/NCI NIH HHS/ -- R01 AI105343/AI/NIAID NIH HHS/ -- R01 CA158186/CA/NCI NIH HHS/ -- R01 CA163739/CA/NCI NIH HHS/ -- R01AI105343/AI/NIAID NIH HHS/ -- R01CA158186/CA/NCI NIH HHS/ -- R01CA163739/CA/NCI NIH HHS/ -- R01CA172651/CA/NCI NIH HHS/ -- T32DK007066/DK/NIDDK NIH HHS/ -- U01AI095608/AI/NIAID NIH HHS/ -- U19 AI082630/AI/NIAID NIH HHS/ -- U19AI082630/AI/NIAID NIH HHS/ -- UL1RR024134/RR/NCRR NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida 33136, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25754329" target="_blank"〉PubMed〈/a〉

Description: CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T(H)2 cytokine-mediated inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263308/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263308/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siracusa, Mark C -- Saenz, Steven A -- Hill, David A -- Kim, Brian S -- Headley, Mark B -- Doering, Travis A -- Wherry, E John -- Jessup, Heidi K -- Siegel, Lori A -- Kambayashi, Taku -- Dudek, Emily C -- Kubo, Masato -- Cianferoni, Antonella -- Spergel, Jonathan M -- Ziegler, Steven F -- Comeau, Michael R -- Artis, David -- AI083480/AI/NIAID NIH HHS/ -- AI61570/AI/NIAID NIH HHS/ -- AI74878/AI/NIAID NIH HHS/ -- AI87990/AI/NIAID NIH HHS/ -- F31 GM082187/GM/NIGMS NIH HHS/ -- F32 AI085828/AI/NIAID NIH HHS/ -- R01 AI061570/AI/NIAID NIH HHS/ -- R01 AI061570-09/AI/NIAID NIH HHS/ -- R01 AI074878/AI/NIAID NIH HHS/ -- R01 AI074878-05/AI/NIAID NIH HHS/ -- R01 AI095466/AI/NIAID NIH HHS/ -- R01 AI095466-02/AI/NIAID NIH HHS/ -- R01 HL107589/HL/NHLBI NIH HHS/ -- R21 AI083480/AI/NIAID NIH HHS/ -- R21 AI083480-02/AI/NIAID NIH HHS/ -- T32 AI060516/AI/NIAID NIH HHS/ -- U01 AI095608/AI/NIAID NIH HHS/ -- U01 AI095608-02/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 14;477(7363):229-33. doi: 10.1038/nature10329.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21841801" target="_blank"〉PubMed〈/a〉

Description: Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4(+) T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-gammat-positive (RORgammat(+)) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORgammat(+) ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4(+) T-cell responses. Consistent with this, selective deletion of MHCII in murine RORgammat(+) ILCs resulted in dysregulated commensal bacteria-dependent CD4(+) T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4(+) T cells that limit pathological adaptive immune cell responses to commensal bacteria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699860/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699860/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hepworth, Matthew R -- Monticelli, Laurel A -- Fung, Thomas C -- Ziegler, Carly G K -- Grunberg, Stephanie -- Sinha, Rohini -- Mantegazza, Adriana R -- Ma, Hak-Ling -- Crawford, Alison -- Angelosanto, Jill M -- Wherry, E John -- Koni, Pandelakis A -- Bushman, Frederic D -- Elson, Charles O -- Eberl, Gerard -- Artis, David -- Sonnenberg, Gregory F -- 2-P30 CA016520/CA/NCI NIH HHS/ -- AI061570/AI/NIAID NIH HHS/ -- AI074878/AI/NIAID NIH HHS/ -- AI087990/AI/NIAID NIH HHS/ -- AI095466/AI/NIAID NIH HHS/ -- AI095608/AI/NIAID NIH HHS/ -- AI095776/AI/NIAID NIH HHS/ -- AI097333/AI/NIAID NIH HHS/ -- AI102942/AI/NIAID NIH HHS/ -- DK071176/DK/NIDDK NIH HHS/ -- DP5 OD012116/OD/NIH HHS/ -- DP5OD012116/OD/NIH HHS/ -- P01 DK071176/DK/NIDDK NIH HHS/ -- P30 DK050306/DK/NIDDK NIH HHS/ -- P30DK50306/DK/NIDDK NIH HHS/ -- R01 AI061570/AI/NIAID NIH HHS/ -- R01 AI074878/AI/NIAID NIH HHS/ -- R01 AI095466/AI/NIAID NIH HHS/ -- R01 AI097333/AI/NIAID NIH HHS/ -- R01 AI102942/AI/NIAID NIH HHS/ -- R21 AI083480/AI/NIAID NIH HHS/ -- R21 AI087990/AI/NIAID NIH HHS/ -- T32 AI007532/AI/NIAID NIH HHS/ -- T32 AI055428/AI/NIAID NIH HHS/ -- T32-AI055428/AI/NIAID NIH HHS/ -- U01 AI095608/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 6;498(7452):113-7. doi: 10.1038/nature12240. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698371" target="_blank"〉PubMed〈/a〉