Journal Articles

beta-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma

PD-1 immune checkpoint inhibitors have produced encouraging results in hepatocellular carcinoma (HCC) patients. However, what determines resistance to anti-PD-1 therapies is unclear. We created a novel genetically-engineered mouse model of HCC that enables interrogating how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;p53-/- HCCs led to T cell-mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;p53-/- HCCs escaped the immune system by upregulating beta-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that beta-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently, impaired T cell activity. Expression of chemokine Ccl5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, beta-catenin-driven tumors were resistant to anti-PD-1. In summary, beta-catenin activation promotes immune escape and resistance to anti-PD-1 and could represent a novel biomarker for HCC patient exclusion.

Author Info: (1) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (2) Oncological Sciences, Icahn School of Medicine at Mount Sinai. (3) Icahn School of Medicine at

Author Info: (1) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (2) Oncological Sciences, Icahn School of Medicine at Mount Sinai. (3) Icahn School of Medicine at Mount Sinai. (4) Oncological Sciences, Icahn School of Medicine at Mount Sinai. (5) Mount Sinai School of Medicine. (6) Liver Diseases, Mt Sinai Liver Cancer program, MSSM. (7) Liver Diseases, Icahn School of Medicine at Mount Sinai. (8) Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai. (9) Icahn School of Medicine at Mount Sinai. (10) Icahn School of Medicine at Mount Sinai. (11) Liver Diseases, Mt Sinai Liver Cancer program, MSSM. (12) Pathology, University of Pittsburgh. (13) Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center. (14) Division of Liver Diseases, Icahn School of Medicine at Mount Sinai. (15) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (16) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai. (17) Oncological Sciences / Immunology Institute, Icahn School of Medicine at Mount Sinai. (18) Pathology and Medicine, University of Pittsburgh Medical Center. (19) Genetics and Genomic Sciences, Mount Sinai School of Medicine. (20) Division of Liver Disease, Mount Sinai School of Medicine. (21) Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai. (22) Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. (23) Oncological Sciences, Icahn School of Medicine at Mount Sinai amaia.lujambio@mssm.edu.

Activation of Mevalonate Pathway via LKB1 Is Essential for Stability of Treg Cells

The function of regulatory T (Treg) cells depends on lipid oxidation. However, the molecular mechanism by which Treg cells maintain lipid metabolism after activation remains elusive. Liver kinase B1 (LKB1) acts as a coordinator by linking cellular metabolism to substrate AMP-activated protein kinase (AMPK). We show that deletion of LKB1 in Treg cells exhibited reduced suppressive activity and developed fatal autoimmune inflammation. Mechanistically, LKB1 induced activation of the mevalonate pathway by upregulating mevalonate genes, which was essential for Treg cell functional competency and stability by inducing Treg cell proliferation and suppressing interferon-gamma and interleukin-17A expression independently of AMPK. Furthermore, LKB1 was found to regulate intracellular cholesterol homeostasis and to promote the mevalonate pathway. In agreement, mevalonate and its metabolite geranylgeranyl pyrophosphate inhibited conversion of Treg cells and enhanced survival of LKB1-deficient Treg mice. Thus, LKB1 is a key regulator of lipid metabolism in Treg cells, involved in optimal programming of suppressive activity, immune homeostasis, and tolerance.

Author Info: (1) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (2) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (3) Institute fo

Author Info: (1) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (2) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (3) Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 67, Mainz 55131, Germany. (4) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (5) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (6) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (7) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (8) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (9) Department of Biomedical Laboratory Science, Daekyeung College, Gyeongsan 38547, Republic of Korea. (10) College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea. (11) Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea. (12) Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea. (13) Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea. (14) New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea. (15) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (16) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. (17) Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. (18) Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Str. 67, Mainz 55131, Germany. Electronic address: waisman@uni-mainz.de. (19) College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address: jchang@yu.ac.kr.

Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity

Agonistic antibodies targeting the tumor necrosis factor (TNF) superfamily of co-stimulatory receptors (TNFRSF) are progressing through various stages of clinical development for cancer treatment, but the desired and defining features of these agents for optimal biological activity remain controversial. One idea, based on recent studies with CD40, is that non-ligand-blocking antibodies targeting membrane-distal cysteine-rich domain 1 (CRD1) have superior agonistic activities compared with ligand-blocking antibodies targeting more membrane-proximal CRDs. Here, we determined the binding and functional characteristics of a panel of antibodies targeting CRDs 1-4 of OX40 (also known as TNFRSF4 or CD134). In striking contrast to CD40, we found that ligand-blocking CRD2-binding and membrane-proximal CRD4-binding anti-OX40 antibodies have the strongest agonistic and anti-tumor activities. These findings have important translational implications and further highlight that the relationship between epitope specificity and agonistic activity will be an important issue to resolve on a case-by-case basis when optimizing antibodies targeting different co-stimulatory tumor necrosis factor receptors (TNFRs).

Author Info: (1) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (2) Cancer Immunology Discovery, Oncology R

Author Info: (1) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (2) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (3) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (4) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (5) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (6) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (7) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (8) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (9) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (10) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (11) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (12) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. (13) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. Electronic address: shahram.salek-ardakani@pfizer.com. (14) Cancer Immunology Discovery, Oncology Research and Development, Pfizer, Inc., 230 E. Grand Ave., South San Francisco, CA 94080, USA. Electronic address: yeungyik@yahoo.com.

Tumor lymphatic function regulates tumor inflammatory and immunosuppressive microenvironments

Proliferation of aberrant, dysfunctional lymphatic vessels around solid tumors is a common histologic finding. Studies have shown that abnormalities in lymphatic function result in accumulation of inflammatory cells with an immunosuppressive profile. We tested the hypothesis that dysfunctional lymphatic vessels surrounding solid tumor regulate changes in the tumor microenvironment and tumor-specific immune responses. Using subcutaneously implanted mouse melanoma and breast cancer tumors in a lymphatic endothelial cell-specific diphtheria toxin receptor transgenic mouse, we found that local ablation of lymphatic vessels increased peritumoral edema, as compared with controls. Comparative analysis of the peritumoral fluid demonstrated increases in the number of macrophages, CD4+ inflammatory cells, F4/80+/Gr-1+ (myeloid derived suppressor cells), CD4+/Foxp3+ (T regs) immunosuppressive cells and expression of inflammatory cytokines such as TNFalpha, IFNgamma and IL1beta following lymphatic ablation. Tumors grown in lymphatic ablated mice exhibited reduced intratumoral accumulation of cytotoxic T cells and increased tumor PD-L1 expression, causing rapid tumor growth, compared with tumors grown in nonlymphatic-ablated mice. Our study suggests that lymphatic dysfunction plays a role in regulating tumor microenvironments and may be therapeutically targeted in combination with immunotherapy to prevent tumor growth and progression.

Author Info: (1) Surgery, Memorial Sloan Kettering Cancer Center katarur@mskcc.org. (2) Surgery, Memorial Sloan Kettering Cancer Center. (3) Surgery, Memorial Sloan Kettering Cancer Center. (4)

Author Info: (1) Surgery, Memorial Sloan Kettering Cancer Center katarur@mskcc.org. (2) Surgery, Memorial Sloan Kettering Cancer Center. (3) Surgery, Memorial Sloan Kettering Cancer Center. (4) Surgery, Memorial Sloan Kettering Cancer Center. (5) Surgery, Memorial Sloan Kettering Cancer Center. (6) Surgery, Memorial Sloan Kettering Cancer Center. (7) Biotechnology Porgramme, Spanish National Cancer Research Centre. (8) Department of Pediatrics, Cornell University Weill Medical College. (9) Surgery, Memorial Sloan Kettering Cancer Center.

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Despite initial complete remission rates of up to 90%, long-term, disease-free survival remains poor in patients with newly diagnosed acute lymphoblastic leukemia (ALL). Response to salvage chemotherapy is suboptimal; therefore, novel therapeutic agents are being investigated in order to improve outcomes in these patients. Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of adults with relapsed or refractory B-cell precursor ALL. Inotuzumab ozogamicin improves response rate, minimal residual disease negativity, and survival compared to standard chemotherapy in this population. In addition, it offers more opportunities to proceed to an allogeneic stem cell transplant in patients who otherwise may not be candidates.

Author Info: (1) The Arthur G James Cancer Hospital and Solove Research Institute, Columbus, Ohio. (2) The Arthur G James Cancer Hospital and Solove Research Institute, Columbus, Ohio.

Author Info: (1) The Arthur G James Cancer Hospital and Solove Research Institute, Columbus, Ohio. (2) The Arthur G James Cancer Hospital and Solove Research Institute, Columbus, Ohio.

The cancer microbiome

Collectively known as the microbiota, the commensal bacteria and other microorganisms that colonize the epithelial surfaces of our body have been shown to produce small molecules and metabolites that have both local and systemic effects on cancer onset, progression and therapy response. To date, most studies focusing on the microbiome have used traditional preclinical mouse models and identified correlative relationships between microbial species and cancer phenotypes. Now, the profound influence of the microbiota on the efficacy of cancer treatments, such as immunotherapies, has begun to be extensively characterized in humans. Paramount to the development of microbiota-based therapeutics, the next challenge in microbiome research will be to identify individual microbial species that causally affect cancer phenotypes and unravel the underlying mechanisms. In this Viewpoint article, we asked four scientists working on the cancer microbiome for their opinions on the current state of the field, where the research is heading and how we can advance our understanding to rationally design microbial-based therapeutics to transform treatment strategies for patients with cancer.

Author Info: (1) Immunology Department, Weizmann Institute of Science, Rehovot, Israel. eran.elinav@weizmann.ac.il. Cancer-Microbiome Division, Deutsches Krebsforschungszentrum (DKFZ), Neuenhei

Author Info: (1) Immunology Department, Weizmann Institute of Science, Rehovot, Israel. eran.elinav@weizmann.ac.il. Cancer-Microbiome Division, Deutsches Krebsforschungszentrum (DKFZ), Neuenheimer Feld 280, Heidelberg, Germany. eran.elinav@weizmann.ac.il. (2) Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. wgarrett@hsph.harvard.edu. Broad Institute of Harvard and MIT, Cambridge, MA, USA. wgarrett@hsph.harvard.edu. Department and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. wgarrett@hsph.harvard.edu. (3) Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Trinchig@mail.nih.gov. (4) Department of Surgical Oncology and Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jwargo@mdanderson.org.

Toll-like Receptor-4 Activation Boosts the Immunosuppressive Properties of Tumor Cells-derived Exosomes

The biology of tumor-derived exosomes (TEX) is only partially understood and much remains to be studied in order to define the effect that the tumor microenvironment or the activation of tumor cells exerts on their composition and functions. Increased expression and activity of toll-like receptor 4 (TLR4) in chronic infectious and inflammatory conditions is related with cancer progression: its activation induces an inflammatory signaling that increases the tumorigenic potential of cancer cells promoting their immune evasion. We investigated the immune modulatory properties of TEX released upon cell TLR4 activation, and we found that, although differences were observed depending on the type of the tumor, the treatment influences TEX composition and boosts their immunosuppressive ability. Our results suggest that the activation of TLR4 supports tumor progression by stimulating the release of more effective immunosuppressive exosomes, which allow tumor cells to escape immune surveillance and probably even play a role in the metastatic process.

Author Info: (1) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. (2) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. (3) Di

Author Info: (1) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. (2) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. (3) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. (4) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. Istituto di Patologia Clinica, Azienda Sanitaria Universitaria Integrata di Udine (ASUID), Udine, Italy. (5) NantBioScience, Inc Culver City, CA, 90232, USA. (6) NantBioScience, Inc Culver City, CA, 90232, USA. (7) Dipartimento di Area Medica (DAME), Universita degli Studi di Udine, Udine, Italy. francesco.curcio@uniud.it. Istituto di Patologia Clinica, Azienda Sanitaria Universitaria Integrata di Udine (ASUID), Udine, Italy. francesco.curcio@uniud.it.

LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8(+) T cell tumor-infiltration impairing anti-PD1 therapy

Cancer response to immunotherapy depends on the infiltration of CD8(+) T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8(+) T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8(+) T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.

Author Info: (1) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. CIBERONC, 028029, Madrid, Spain. (2) Vall d Hebron Institute of Oncology

Author Info: (1) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. CIBERONC, 028029, Madrid, Spain. (2) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. CIBERONC, 028029, Madrid, Spain. (3) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (4) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (5) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (6) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (7) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (8) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (9) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (10) Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. Universitat Autonoma de Barcelona, 08193, Cerdanyola del Valles, Spain. (11) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (12) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (13) Hospital Clinic, University of Barcelona and Institut d'Investigacio Biomedica August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain. (14) Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Center, CNIO, 28029, Madrid, Spain. (15) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (16) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (17) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. (18) Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Center, CNIO, 28029, Madrid, Spain. (19) Hospital Clinic, University of Barcelona and Institut d'Investigacio Biomedica August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain. (20) Hospital Clinic, University of Barcelona and Institut d'Investigacio Biomedica August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain. (21) Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. Universitat Autonoma de Barcelona, 08193, Cerdanyola del Valles, Spain. (22) Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. Universitat Autonoma de Barcelona, 08193, Cerdanyola del Valles, Spain. (23) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. CIBERONC, 028029, Madrid, Spain. Universitat Autonoma de Barcelona, 08193, Cerdanyola del Valles, Spain. (24) Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. jseoane@vhio.net. CIBERONC, 028029, Madrid, Spain. jseoane@vhio.net. Universitat Autonoma de Barcelona, 08193, Cerdanyola del Valles, Spain. jseoane@vhio.net. Institucio Catalana de Recerca i Estudis Avancats (ICREA), 08010, Barcelona, Spain. jseoane@vhio.net.

Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8(+) T Cell Apoptosis

Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8(+) T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8(+) T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8(+) tumor-infiltrating lymphocyte apoptosis through regulating IFN-gamma production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8(+) T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.

Author Info: (1) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Jian.Qiao@UTSouthwestern.edu. (2) The Department of Pat

Author Info: (1) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Jian.Qiao@UTSouthwestern.edu. (2) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (3) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (4) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (5) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (6) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (7) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (8) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. (9) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (10) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (11) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (12) Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. Electronic address: tingxu@alphamab.com. (13) The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Yang-Xin.Fu@UTSouthwestern.edu.

Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8(+) T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-gamma-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-gamma. The cooperation between tumor-derived CCL5 and IFN-gamma-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

Author Info: (1) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (2) Ludwig Institute for Cancer Research and Department of

Author Info: (1) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (2) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (3) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (4) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (5) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. (6) Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; University of Chicago, Knapp Center for Biomedical Discovery, Department of Hematology & Oncology, Chicago, IL 60637, USA. (7) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (8) Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Cell and Gene Therapy, OTAT/CBER/FDA, Silver Spring, MD 20993, USA. (9) Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (10) Russ College of Engineering and Technology, Ohio University, Athens, OH 45701, USA. (11) Department of Immunology and Gynecologic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA. (12) SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; International Microbiome Centre, University of Calgary, Calgary, AB, Canada. (13) Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (14) Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (15) Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (16) Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (17) Bristol-Myers Squibb, Princeton, NJ 08540, USA. (18) Laura and Isaac Perlmutter Cancer Center, New York University, 522 First Avenue, Room 1310 Smilow Building, New York, NY 10016, USA. (19) Department of Pathology, Brigham & Women's Hospital, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (20) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (21) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (22) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (23) Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (24) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland; 2nd Department of Pathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens 12464, Greece. (25) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. (26) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland; SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. (27) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne 1066, Switzerland. Electronic address: george.coukos@chuv.ch.

Close Modal