title: Targeting tumor-associated immune suppression with selective protein kinase A type I (PKAI) inhibitors may enhance cancer immunotherapy.
abstract: Despite the tremendous progress in last few years, the cancer immunotherapy has not yet improved disease-free because of the tumor-associated immune suppression being a major barrier. Novel trends to enhance cancer immunotherapy aims at harnessing the therapeutic manipulation of signaling pathways mediating the tumor-associated immune suppression, with the general aims of: (a) reversing the tumor immune suppression; (b) enhancing the innate and adaptive components of anti-tumor immunosurveillance, and (c) protecting immune cells from the suppressive effects of T regulatory cells (Tregs) and the tumor-derived immunoinhibitory mediators. A particular striking example in this context is the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A type I (PKAI) pathway. Oncogenic cAMP/PKAI signaling has long been implicated in the initiation and progression of several human cancers. Emerging data indicate that cAMP/PKAI signaling also contributes to tumor- and Tregs-derived suppression of innate and adaptive arms of anti-tumor immunosurveillance. Therapeutically, selective PKAI inhibitors have been developed which have shown promising anti-cancer activity in pre-clinical and clinical settings. Rp-8-Br-cAMPS is a selective PKAI antagonist that is widely used as a biochemical tool in signal transduction research. Collateral data indicate that Rp-8-Br-cAMPS has shown immune-rescuing potential in terms of enhancing the innate and adaptive anti-tumor immunity, as well as protecting adaptive T cells from the suppressive effects of Tregs. Therefore, this proposal specifically implicates that combining selective PKAI antagonists/inhibitors with cancer immunotherapy may have multifaceted benefits, such as rescuing the endogenous anti-tumor immunity, enhancing the efficacy of cancer immunotherapy, and direct anti-cancer effects.
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: muzammal@gibh.ac.cn.
authors.forename: Muzammal
authors.initials: M
authors.lastname: Hussain
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Shah
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Nasir
authors.initials: N
authors.lastname: Abbas
authors.affiliation: Immunopharmacology Laboratory, Department of Pharmacology & Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan.
authors.forename: Aqeel
authors.initials: A
authors.lastname: Javeed
authors.affiliation: AM/PM Veterinary Hospital, 4872 Olinda St., Yorba Linda, CA 92886, United States.
authors.forename: Muhammad Mahmood
authors.initials: MM
authors.lastname: Mukhtar
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, PR China; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Jiancun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D018448:Models, Immunological; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054743:Cyclic AMP-Dependent Protein Kinase Type I