Journal Articles

Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination

Spotlight 

Yu and Green et al. showed that in patients with several types of carcinomas, liver metastasis was associated with poor response to immunotherapy, reduced T cells in the periphery and primary tumors, and limited intratumoral T cell diversity. In anti-PD-L1-responsive mouse s.c. tumor models, liver metastasis voided tumor-specific anti-PD-L1 efficacy. Activated antigen-specific CD44+LFA-1+Fas+CD8+ T cells accumulated in livers, but not s.c. tumors nor their draining lymph nodes. Hepatic FasL+ monocyte-derived macrophages induced Fas-mediated tumor-specific T cell death. Hepatic radiotherapy altered the hepatic chemokine content and rescued the immunotherapy response.

Contributed by Paula Hochman

Yu and Green et al. showed that in patients with several types of carcinomas, liver metastasis was associated with poor response to immunotherapy, reduced T cells in the periphery and primary tumors, and limited intratumoral T cell diversity. In anti-PD-L1-responsive mouse s.c. tumor models, liver metastasis voided tumor-specific anti-PD-L1 efficacy. Activated antigen-specific CD44+LFA-1+Fas+CD8+ T cells accumulated in livers, but not s.c. tumors nor their draining lymph nodes. Hepatic FasL+ monocyte-derived macrophages induced Fas-mediated tumor-specific T cell death. Hepatic radiotherapy altered the hepatic chemokine content and rescued the immunotherapy response.

Contributed by Paula Hochman

ABSTRACT: Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.

Author Info: (1) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. (2) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center,

Author Info: (1) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. (2) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (3) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. migr@med.umich.edu. (4) Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. migr@med.umich.edu. (5) Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA. migr@med.umich.edu. (6) Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA. (7) Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. (8) Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. (9) University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA. (10) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. (11) Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. (12) Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. (13) Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. (14) Machine Learning Department, Moffitt Cancer Center, Tampa, FL, USA. (15) University of Michigan School of Public Health, Ann Arbor, MI, USA. (16) Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA. (17) Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA. (18) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu. (19) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. wzou@med.umich.edu. (20) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu. (21) Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA. wzou@med.umich.edu. (22) Graduate Program in Cancer Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu.

Randomized phase II trial of sipuleucel-T with or without radium-223 in men with bone-metastatic castration-resistant prostate cancer

PURPOSE: To investigate if radium-223 increases peripheral immune responses to sipuleucel-T in men with bone-predominant, minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: 32 patients were randomized 1:1 in this open label, phase 2 multicenter trial. Patients in the control arm received 3 sipuleucel-T treatments, 2 weeks apart. Those in the combination arm received 6 doses of radium-223 monthly, with sipuleucel-T intercalated between the second and fourth doses of radium-223. The primary endpoint was a comparison of peripheral antigen PA2024-specific T cell responses (measured by proliferation index). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and PSA responses. RESULTS: We enrolled 32 patients, followed for a median of 1.6 years. Six weeks after the first sipuleucel-T dose, participants in the control arm had a 3.2-fold greater change in PA2024-specific T cell responses compared to those who received combination treatment (p=0.036). Patients in the combination arm were more likely to have a >50% PSA decline (5 (31%) versus 0 patients; P=0.04), and also demonstrated longer PFS (39 vs 12 weeks; HR 0.32; 95% CI 0.14-0.76) and OS (not-reached vs 2.6 years; HR 0.32; 95% CI 0.08-1.23). CONCLUSION: Our data raise the possibility of greater clinical activity with the combination of sipuleucel-T and radium-223 in men with asymptomatic bone mCRPC, despite the paradoxically lower immune responses observed. Additional study to confirm these findings in a larger trial is warranted.

Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. (2) Oncology, Johns Hopkins University School of Medicine. (3) Biostatistics and Bio

Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. (2) Oncology, Johns Hopkins University School of Medicine. (3) Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center. (4) Hematology and Oncology, Massachusetts General Hospital. (5) Radiation Oncology, Johns Hopkins University School of Medicine. (6) Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine. (7) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. (8) Oncology, Sidney Kimmel Comprehensive Cancer Center. (9) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. (10) Divisions of Medical Oncology and Urology, Departments of Medicine and Surgery, Duke Cancer Institute. (11) Tulane Medical Center. (12) Medicine and Urology, Tulane University. (13) Urologic Oncology Program, Cedars-Sinai Medical Center. (14) Deming Department of Medicine, Tulane University. (15) Department of Urology, and the Columbia Center for Translational Immunology (CCTI), Columbia University Herbert Irving Comprehensive Cancer Center. (16) Urologic Oncology Program & Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center. (17) Divisions of Medical Oncology and Urology, Departments of Medicine and Surgery, Duke Cancer Institute. (18) Medicine and Urology, Tulane University School of Medicine. (19) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine eantona1@jhmi.edu.

Guidance Document: Validation of a High-Performance Liquid Chromatography-Tandem Mass Spectrometry Immunopeptidomics Assay for the Identification of HLA Class I Ligands Suitable for Pharmaceutical Therapies

For more than two decades naturally presented, human leukocyte antigen (HLA)-restricted peptides (immunopeptidome) have been eluted and sequenced using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Since, identified disease-associated HLA ligands have been characterized and evaluated as potential active substances. Treatments based on HLA-presented peptides have shown promising results in clinical application as personalized T cell-based immunotherapy. Peptide vaccination cocktails are produced as investigational medicinal products under GMP conditions. To support clinical trials based on HLA-presented tumor-associated antigens, in this study the sensitive LC-MS/MS HLA class I antigen identification pipeline was fully validated for our technical equipment according to the current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The immunopeptidomes of JY cells with or without spiked-in, isotope labeled peptides, of peripheral blood mononuclear cells of healthy volunteers as well as a chronic lymphocytic leukemia and a bladder cancer sample were reliably identified using a data-dependent acquisition method. As the LC-MS/MS pipeline is used for identification purposes, the validation parameters include accuracy, precision, specificity, limit of detection and robustness.

Author Info: (1) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany; Natural and Medical Science Institute at the University of TŸbingen (NMI), Reut

Author Info: (1) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany; Natural and Medical Science Institute at the University of TŸbingen (NMI), Reutlingen, Germany. (2) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany. (3) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany. (4) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany. (5) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany; German Cancer Research Center (DKFZ) partner site and German Cancer Consortium (DKTK) TŸbingen, TŸbingen, Germany. (6) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany; Immatics Biotechnologies GmbH, TŸbingen, Germany. (7) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany; German Cancer Research Center (DKFZ) partner site and German Cancer Consortium (DKTK) TŸbingen, TŸbingen, Germany. (8) Department of Immunology, Institute for Cell Biology, University of TŸbingen, TŸbingen, Germany; German Cancer Research Center (DKFZ) partner site and German Cancer Consortium (DKTK) TŸbingen, TŸbingen, Germany. Electronic address: stefan.stevanovic@uni-tuebingen.de.

Immune Functions of Signaling Lymphocytic Activation Molecule Family Molecules in Multiple Myeloma

The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated protein (SAP) or Ewing's sarcoma-associated transcript 2 (EAT-2), which target immunoreceptor tyrosine-based switch motifs in the cytoplasmic regions of the receptors. Notably, SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly and constitutively expressed on MM cells that do not express the adaptor proteins SAP and EAT-2. This review summarizes recent studies on the expression and biological functions of SLAM family receptors during the malignant progression of MM and the resulting preclinical and clinical research involving four SLAM family receptors. A better understanding of the relationship between SLAM family receptors and MM disease progression may lead to the development of novel immunotherapies for relapse prevention.

Author Info: (1) Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan. (2) Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, J

Author Info: (1) Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan. (2) Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan. (3) Division of Diabetes, Endocrinology and Hematology, Department of Internal Medicine, Dokkyo Medical University Saitama Medical Center, Saitama 343-8555, Japan. Department of Hematology, Nippon Medical School, Tokyo 113-8602, Japan.

Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in two murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-_-producing tumor antigen-specific CD8(+) T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expressions of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H(2) O(2) , an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-_ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31(+) tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-_ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H(2) O(2) -associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.

Author Info: (1) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. Division of General Thoracic Surgery, Department of Surgery, Keio U

Author Info: (1) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. Division of General Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan. (2) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh. (3) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. (4) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. (5) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. (6) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan. (7) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. (8) Department of Ophthalmology, Keio University School of Medicine. (9) Division of General Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan. (10) Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine. Department of Immunology, School of Medicine, International University of Health and Welfare, Chiba, Japan.

Fueling the Fire: Inflammatory Forms of Cell Death and Implications for Cancer Immunotherapy

Unleashing the immune system with immune checkpoint inhibitors (ICI) has significantly improved overall survival for subsets of patients with stage III/IV cancer. However, many tumors are nonresponsive to ICIs, in part due to a lack of tumor-infiltrating lymphocytes (TIL). Converting these immune "cold" tumors to "hot" tumors that are thus more likely to respond to ICIs is a major obstacle for cancer treatment. Triggering inflammatory forms of cell death, such as necroptosis and pyroptosis, may alter the tumor immune microenvironment and the influx of TILs. We present an emerging view that promoting tumor-localized necroptosis and pyroptosis may ultimately enhance responses to ICI. SIGNIFICANCE: Many tumor types respond poorly to ICIs or respond but subsequently acquire resistance. Effective therapies for ICI-nonresponsive tumors are lacking and should be guided by evidence from preclinical studies. Promoting inflammatory cell death mechanisms within the tumor may alter the local immune microenvironment toward an ICI-responsive state.

Author Info: (1) Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. (2) Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania

Author Info: (1) Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. (2) Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. (3) Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.aplin@jefferson.edu. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.

Therapeutic vaccination targeting CD40 and TLR3 controls melanoma growth through existing intratumoral CD8 T cells without new T cell infiltration

Dendritic cells are potently activated by the synergistic action of CD40 stimulation in conjunction with signaling through toll like receptors, subsequently priming T cells. Cancer vaccines targeting the activation of dendritic cells in this manner show promise in murine models and are being developed for human patients. While the efficacy of vaccines based on CD40 and toll like receptor stimulation has been established, further investigation is needed to understand the mechanism of tumor control and how vaccination alters tumor infiltrating immune cells. In this study we vaccinated mice bearing established murine melanoma tumors with agonistic anti-CD40, polyI:C, and tumor antigen. Vaccination led to increased intratumoral T cell numbers and delayed tumor growth, yet did not require trafficking of T cells from the periphery. Pre-existing intratumoral T cells exhibited an acute burst in proliferation but became less functional in response to vaccination. However, the increased intratumoral T cell numbers yielded increased numbers of effector T cells per tumor. Together, our data indicate that the existing T cell response and intratumoral dendritic cells are critical for vaccination efficacy. It also suggests that circulating T cells responding to vaccination may not be an appropriate biomarker for vaccine efficacy.

Author Info: (1) Department of Pathology, University of Virginia, Charlottesville, VA, USA. (2) Department of Pathology, University of Virginia, Charlottesville, VA, USA. tb5v@virginia.edu.

Author Info: (1) Department of Pathology, University of Virginia, Charlottesville, VA, USA. (2) Department of Pathology, University of Virginia, Charlottesville, VA, USA. tb5v@virginia.edu.

At the Crossroads: COVID-19 and Immune Checkpoint Blockade for Cancer

The immunomodulatory effects of immune checkpoint blockade (ICB) therapy for cancer may act at the crossroads between the need to increase anti-viral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and to decrease the inflammatory responses in severe cases of coronavirus disease 2019 (COVID-19). There is evidence from preclinical models that blocking programmed death receptor 1 (PD1) protects against RNA virus infections, which suggests that patients with cancer receiving ICB may have lower rates of viral infection. However, given the heterogeneity of patient characteristics, this would be difficult to demonstrate using population-based registries or in clinical trials. Most studies of the impact of ICB therapy on the course of COVID-19 have centered in studying its potential detrimental impact on the course of the COVID-19 infection, in particular on the development of the most severe inflammatory complications. This is a logical concern as it is becoming clear that complications of COVID-19 such as severe respiratory distress syndrome are related to interferon signaling, which is the pathway that leads to expression of the PD1 ligand PD-L1. Therefore, PD1/PDL1 ICB could potentially increase inflammatory processes, worsening the disease course for patients. However, review of the current evidence does not support the notion that ICB therapy worsens complications from COVID-19, and we conclude that it supports the continued use of ICB therapy during the COVID-19 pandemic provided that we now collect data on the effects of such therapy on COVID-19 vaccination.

Author Info: (1) Department of Medicine, Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles aribas@mednet.ucla.edu. (2) Unit of Thoracic Oncology, Departm

Author Info: (1) Department of Medicine, Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles aribas@mednet.ucla.edu. (2) Unit of Thoracic Oncology, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori.

Nanodrug with dual-sensitivity to tumor microenvironment for immuno-sonodynamic anti-cancer therapy

Although a combination with photodynamic therapy (PDT) is a potential means to improve the immune checkpoint blockade (ICB)-based anticancer immunotherapy, this strategy is subjected to the extremely poor light penetration in melanoma. Herein, we develop a lipid (LP)-based micellar nanocarrier encapsulating sonosensitizer chlorin e6 (Ce6) in the core, conjugating anti-PD-L1 antibody (aPD-L1) to the interlayer through MMP-2-cleavable peptide, and bearing a PEG coating sheddable at low pH value (Å6.5) of tumor microenvironment. The unique nanocarrier design allows a tumor-targeting delivery to activate the anti-tumor immunity and meanwhile to reduce immune-related adverse effects (irAEs). Moreover, a sonodynamic therapy (SDT) is triggerable by using ultrasonic insonation to produce tumor-killing reactive oxygen species (ROS), thereby bypassing the poor light penetration which restricts PDT in melanoma. A combination of SDT with aPD-L1 immunotherapy effectively promotes tumor infiltration and activation of cytotoxic T cells, which resulted in robust anti-cancer immunity and long-term immune memory to effectively suppress melanoma growth and postoperative recurrence. This strategy for tumor-targeting codelivery of immune checkpoint inhibitors and SDT agents could be readily extended to other tumor types for better immunotherapeutic outcome and reduced irAEs.

Author Info: (1) College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China. (2) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun

Author Info: (1) College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China. (2) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China. (3) Department of Minimally Invasive Interventional Radiology, and Laboratory of Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510275, China. (4) Department of Minimally Invasive Interventional Radiology, and Laboratory of Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510275, China. (5) Department of Medical Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. (6) College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China. Electronic address: wangy488@jnu.edu.cn. (7) Department of General Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510275, China. Electronic address: guoyu35@mail.sysu.edu.cn. (8) College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China; PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China. Electronic address: shuaixt@mail.sysu.edu.cn.

SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFN_ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.

Author Info: (1) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (2) Oncology Disease Area, Novartis Institutes for BioM

Author Info: (1) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (2) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (3) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (4) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (5) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (6) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (7) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (8) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (9) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (10) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (11) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (12) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (13) Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Cambridge, USA. (14) Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Cambridge, USA. (15) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (16) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (17) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (18) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (19) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (20) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (21) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (22) Analytical Sciences & Imaging, Novartis Institutes for BioMedical Research, Cambridge, USA. (23) Analytical Sciences & Imaging, Novartis Institutes for BioMedical Research, Cambridge, USA. (24) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (25) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (26) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (27) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (28) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (29) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (30) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (31) Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, USA. (32) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (33) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (34) Oncology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland. (35) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (36) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (37) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (38) Analytical Sciences & Imaging, Novartis Institutes for BioMedical Research, Cambridge, USA. (39) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (40) Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Cambridge, USA. (41) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (42) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (43) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (44) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (45) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (46) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. (47) Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. bill.hastings@novartis.com. (48) Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. s.goldoni22@gmail.com.

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