STAT3 A Target to Enhance Antitumor Immune Response

Heehyoung Lee, Sumanta Kumar Pal, Karen Reckamp, Robert A. Figlin, and Hua Yu

Contents

1 Introduction 42

2 Stat3-Mediated Immune Suppression 43

2.1 Inhibition of the Th1 Immune Response 43

2.2 Relevant Immunologic Signaling Pathways 45

2.3 Role in Myeloid Derived Suppressor Cells 46

2.4 Role in Regulatory T-Cells 47

3 Therapeutic Relevance 48

3.1 Genetic Evidence and Potential Toxicity 49

3.2 JAK Inhibitors 49

3.3 Other Oncogenic Kinase Inhibitors 50

3.4 RTK Inhibitors 51

4 Concluding Remarks 53

References 53

Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA S.K. Pal

Division of Genitourinary Malignancies, Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA K. Reckamp

Division of Thoracic Malignancies, Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA

R.A. Figlin

Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA H. Yu (*)

Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA e-mail: [email protected]

G. Dranoff (ed.), Cancer Immunology and Immunotherapy, 41

Current Topics in Microbiology and Immunology 344, DOI 10.1007/82_2010_51 © Springer-Verlag Berlin Heidelberg 2011, published online: 2 June 2010

Abstract Signal transducer and activator of transcription 3 (Stat3) has emerged as a critical regulator for tumor-associated inflammation. Activation of Stat3 negatively regulates the Thl-type immune response and promotes expansion of myeloid-derived suppressor cells (MDSCs) and regulatory T-cell functions in the tumor microenvironment. Mounting evidence suggests that Stat3 and related pathways may serve as a target for changing the tumor immunologic microenvironment to benefit cancer immunotherapies. Many recent studies support the use of certain tyrosine kinase inhibitors, through inhibition of Stat3, in decreasing immunosuppression in the tumor microenvironment. Other potential therapeutic avenues include the use of targeted delivery of Stat3 siRNA into immune cells. Here, we describe the role of Stat3 in regulating the immunologic properties of tumors as a background for Stat3-based therapeutic interventions.

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