Massachusetts Institute of Technology

The Broad Institute, Inc.

The Brigham and Women's Hospital, Inc.

Harvard College

Dana-farber-cancer Institute Inc.

The General Hospital Corporation

University of California

Other

Yale University

Children's Medical Center Corporation

Quark Pharmaceuticals, Inc.

Quark Biotech, Inc.

The Board Institute, Inc.

Aviv Regev

Vijay K Kuchroo

Ana Carrizosa Anderson

Orit Rozenblatt-Rosen

Alexander K Shalek

Jellert Gaublomme

Hongkun Park

Chao Wang

Meromit Singer

Feng Zhang

Asaf Madi

Anindita Basu

David A Weitz

Le Cong

Asaf Rotem

Karthik Shekhar

Steven Andrew McCarroll

Rebecca H Herbst

Itay Tirosh

Evan Macosko

Benjamin Izar

Moshe Biton

Brian Cleary

Nir Yosef

Christopher B Ford

Elena Feinstein

Eric Lander

Nir Hacohen

Ramnik Xavier

Paz Einat

Rami Skaliter

Eric S Lander

Jose Ordovas-Montanes

Joshua Asher Weinstein

Jason Daniel Buenrostro

Nandini Acharya

Mario Suva

Samantha J Riesenfeld

Rahul Satija

Naomi Habib

Christopher Smillie

Monika S Kowalczyk

Norio Chihara

Oren Parnas

Adam Haber

Ayshwarya Subramanian

Livnat Jerby

Youjin Lee

James Joseph Collins

Richard A Flavell

Omar O Abudayyeh

Jonathan S Gootenberg

Hagar Kalinski

Kai W Wucherpfennig

Levi A Garraway

Bradley Bernstein

Tyler E Jacks

Jonathan S Weissman

Constance L Cepko

Yinqing Li

Vijay G Sankaran

Thomas W Norman

Matthias Heidenreich

Kevin Struhl

Lukasz Swiech

Atray Dixit

David A Canner

Joshua Sanes

Nathan D Mathewson

Volker Hovestadt

Amy Li

Sylvain Lapan

Paola Arlotta

Irene Whitney

Eugene Drokhlyansky

Leif S Ludwig

Xin Jin

Patrick R Burkett

Antonia Wallrapp

Davide Mangani

Linglin Huang

Inbal Avraham-Davidi

Nicole C Joller

Johanna Klughammer

Bo Li

Brittany Adamson

Chuan Wu

Daniel Abravanel

Jacob C Ulirsch

Kathryn Geiger-Schuller

Christoph Muus

Caleb A Lareau

Sean Simmons

Jayaraj Rajagopal

Daniel Montoro

Alexandra Schnell

Matan Hofree

Pratiksha Thakore

Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors. Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. While co-inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co-inhibitory receptors (Tim-3, Lag-3, and TIGIT). The present invention provides a novel immunoregulatory network and novel cell surface molecules that have an inhibitory function in the tumor microenvironment. The present invention further provides the novel discovery that the transcription factors Prdm1 and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module. This critical molecular circuit underlies the expression of co-inhibitory receptors such as ILT-3 in dysfunctional T cells and identifies novel regulators of T cell dysfunction.

Modulation of novel immune checkpoint targets

The present invention is generally directed to a colorectal (CRC) cell atlas that provides methods of predicting outcomes of cancer patients and therapeutic targets for treating patients in need thereof. The atlas may be used to predict a response to immunotherapy, in particular checkpoint blockade therapy and adoptive cell transfer. Disclosed herein are previously unidentified gene programs in tumors that can be used to predict response and provide for therapeutic targets that can be used to shift a tumor to a responsive phenotype.

Methods for predicting outcomes and treating colorectal cancer using a cell atlas

The subject matter disclosed herein is generally directed to methods and compositions for modulating inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors. The subject matter disclosed herein is also generally directed to detecting and monitoring an ILC response. Additionally, the subject matter is directed to treating skin inflammation, such as psoriasis.

Methods and compositions for modulating innate lymphoid cell pathogenic effectors

Provided herein are methods and compositions for identifying ionocytes from respiratory epithelial cells, and uses of such cells for treatment of inflammatory lung disease. Also provided herein are methods and compositions for modulating respiratory tract epithelial cell proliferation, differentiation, maintenance, and/or function.

Respiratory and sweat gland ionocytes

Described herein are methods and uses thereof for in vivo evaluating functions of multiple genes in parallel by combining in utero genetic perturbation of progenitor cells and single-cell transcriptomic profiling of progeny cells in animals. These methods can be used, among other things, to reveal in vivo gene functions in a cell type-specific manner.

Methods of in vivo evaluation of gene function

Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors. Therapeutic blockade of these receptors has clinical efficacy in the treatment of cancer. While co-inhibitory receptors are co-expressed, the triggers that induce them and the transcriptional regulators that drive their co-expression have not been identified. The immunoregulatory cytokine IL-27 induces a gene module in T cells that includes several known co-inhibitory receptors (Tim-3, Lag-3, and TIGIT). The present invention provides a novel immunoregulatory network as well as novel cell surface molecules that have an inhibitory function in the tumor microenvironment. The present invention further provides the novel discovery that the transcription factors Prdm1 and c-Maf cooperatively regulate the expression of the co-inhibitory receptor module. This critical molecular circuit underlies the co-expression of co-inhibitory receptors in dysfunctional T cells and identifies novel regulators of T cell dysfunction.

An atlas of intestinal epithelial cells, intestinal epithelial stem cells and intestinal immune cells identifies new cell populations, markers, networks, and responses to stimuli. Intestinal T cells drive intestinal epithelial cell differentiation and activity. Accordingly, disclosed are methods of modulating intestinal epithelial cell differentiation, maintenance and/or function, related methods for the treatment of disease, including IBD. Also disclosed are methods and kits for identifying cell types, their differentiation, homeostasis and activation.

Modulation of intestinal epithelial cell differentiation, maintenance and/or function through T cell action

Techniques Nuc-seq, Div-Seq, and Dronc-Seq are allow for unbiased analysis of any complex tissue. Nuc-Seq, a scalable single nucleus RNA-Seq method, can sensitively identify closely related cell types, including within the adult hippocampus. Div-seq combines Nuc-Seq with EdU-mediated labeling of proliferating cells, allowing tracking of transcriptional dynamics of newborn neurons in an adult neurogenic region in the hippocampus. Dronc-Seq uses a microfluidic device to co-encapsulate individual nuclei in reverse emulsion aqueous droplets in an oil medium together with one uniquely barcoded mRNA-capture bead.

Methods for determining spatial and temporal gene expression dynamics during adult neurogenesis in single cells

The subject matter disclosed herein is generally directed to tissue specific modulation of Th17 differentiation and pathogenicity by targeting tissue specific Th17 gene programs and gene targets. The tissue specific modulation may be used therapeutically to treat a disease or condition in the tissue where it arises. The subject matter disclosed herein is also directed to detecting tissue specific Th17 cells for diagnostic and therapeutic methods.

Compositions and methods for modulating and detecting tissue specific TH17 cell pathogenicity

The subject matter disclosed herein is generally directed to compositions and methods for treating diffuse gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-gliomas). Disclosed herein are gene signatures specific for tumor cell types and compositions for treatment of H3K27M gliomas. In one embodiment, PRC1 is targeted in a treatment regimen for H3K27M-gliomas.

Methods and compositions for targeting developmental and oncogenic programs in H3K27M gliomas

The present invention relates to tissue and cell imaging utilizing genomic informatics and gene-expression profiling. Gene-expression profiles utilized in methods to obtain in situ imaging of cells and tissues provide complex molecular fingerprints regarding the relative state of a cell or tissue.

Compressed sensing for screening and tissue imaging

Computational and functional analysis identified the neuropeptide receptor Nmur1 as selectively expressed on Type 2 innate lymphoid cells (ILC2s). While both IL-33 and IL-25 promote ILC activation in vivo, IL-33 induces robust ILC proliferation, whereas ILCs activated with IL-25 do not proliferate as robustly and up-regulate Nmur1 expression. Treatment with neuromedin U (NMU), the neuropeptide ligand of Nmur1, had little effect on its own. Co-administration of IL-25 with NMU, however, dramatically amplified allergic lung inflammation and induced the proliferation and expansion of specific ILC2 subsets, characterized by a molecular signature unique to pro-inflammatory ILC2s. The results demonstrate that Nmur1 signaling strongly modulates IL-25-mediated ILC2 responses, resulting in highly proliferative pro-inflammatory ILCs, and highlights the importance of neuro-immune crosstalk in allergic inflammatory responses at mucosal surfaces.

Methods and compositions for regulating innate lymphoid cell inflammatory responses

The present invention discloses novel methods and uses thereof for producing molecular spatial maps of metastatic breast cancer (MBC) and ductal carcinoma in situ of the breast (DCIS). A specific list of genes are identified using single-cell RNA sequencing and single-nucleus RNA sequencing and are used for RNA visualization of MBC and DCIS tissue microenvironment. Unexpected subtypes of tumor cells are revealed, and methods for identifying molecular biomarkers for MBC in the bone and breast and DCIS are disclosed. Furthermore, methods for identifying therapeutic agents and uses thereof for treating MBC and DCIS as well as compositions thereof comprising such identified therapeutic agents are provided.

Molecular spatial mapping of metastatic tumor microenvironment

The present invention provides for a human cell atlas of the colon from healthy and diseased subjects. The atlas was obtained by single sequencing of about 117,000 cells. The present invention discloses novel markers for cell types. Moreover, genes associated with disease are identified in the colon and colon specific cell types. The invention provides for diagnostic assays based on gene markers and cell composition, as well as target cell types that express genes associated with disease. Finally, disclosed are novel cell types and methods of quantitating, detecting and isolating the cell types.

Cell atlas of the healthy and ulcerative colitis human colon

Transcriptomes of individual neurons provide rich information about cell types and dynamic states. However, it is difficult to capture rare dynamic processes, such as adult neurogenesis, because isolation from dense adult tissue is challenging, and markers for each phase are limited. Here, Applicants developed Nuc-seq, Div-Seq, and Dronc-Seq. Div-seq combines Nuc-Seq, a scalable single nucleus RNA-Seq method, with EdU-mediated labeling of proliferating cells. Nuc-Seq can sensitively identify closely related cell types within the adult hippocampus. Div-Seq can track transcriptional dynamics of newborn neurons in an adult neurogenic region in the hippocampus. Dronc-Seq uses a microfluidic device to co-encapsulate individual nuclei in reverse emulsion aqueous droplets in an oil medium together with one uniquely barcoded mRNA-capture bead. Finally, Applicants found rare adult newborn GABAergic neurons in the spinal cord, a non-canonical neurogenic region. Taken together, Nuc-Seq, Div-Seq and Dronc-Seq allow for unbiased analysis of any complex tissue.

Methods for determining spatial and temporal gene expression dynamics in single cells

Growing community of inventors

Cambridge, MA, United States of America

Aviv Regev