A high‐throughput RNA i screen for detection of immune‐checkpoint molecules that mediate tumor resistance to cytotoxic T lymphocytes

Abstract

The success of T cell-based cancer immunotherapy is limited by tumor's resistance against killing by cytotoxic T lymphocytes (CTLs). Tumor-immune resistance is mediated by cell surface ligands that engage immune-inhibitory receptors on T cells. These ligands represent potent targets for therapeutic inhibition. So far, only few immune-suppressive ligands have been identified. We here describe a rapid high-throughput siRNA-based screening approach that allows a comprehensive identification of ligands on human cancer cells that inhibit CTL-mediated tumor cell killing. We exemplarily demonstrate that CCR9, which is expressed in many cancers, exerts strong immune-regulatory effects on T cell responses in multiple tumors. Unlike PDL1, which inhibits TCR signaling, CCR9 regulates STAT signaling in T cells, resulting in reduced T-helper-1 cytokine secretion and reduced cytotoxic capacity. Moreover, inhibition of CCR9 expression on tumor cells facilitated immunotherapy of human tumors by tumor-specific T cells in vivo. Taken together, this method allows a rapid and comprehensive determination of immune-modulatory genes in human tumors which, as an entity, represent the ‘immune modulatome’ of cancer.

Thyrotropin-Releasing Hormone (TRH) and Somatostatin (SST), but not Growth Hormone-Releasing Hormone (GHRH) nor Ghrelin (GHRL), Regulate Expression and Release of Immune Growth Hormone (GH) from Chicken Bursal B-Lymphocyte Cultures

“…It has been described that GHRH is the main stimulatory regulator of pituitary GH expression and secretion [47], and it has also been reported to stimulate GH expression in chicken testis [48] and in quail immortalized neuroretinal (QNR/D) cells [49]. The expression of GHRH-R was previously reported in thymocytes and splenocytes of rats [50,51], fish [52], and in human T-lymphocytes [53]. Interestingly, neither GHRH nor GHRH receptor mRNAs, nor GHRH-R protein, were detected in chicken BBLs, in accordance with previous findings, where the absence of GHRH and GHRH-R in the chicken spleen was reported [41,54].…”

Anakoinosis: Communicative Reprogramming of Tumor Systems - for Rescuing from Chemorefractory Neoplasia

“…Classic targeted therapies single out specific rationalizations as important targets for tumor control [ 46 , 47 ]. All these therapies leave out of consideration that rationalizations of hallmarks of cancer may have large variations in their constitution, and are often redundantly organized, such as angiogenesis [ 7 ], inflammation [ 16 , 28 , 48 ], and immune response [ 44 – 46 , 49 ] etc.…”

CCR9 and CCL25: A review of their roles in tumor promotion

“…Unlike PD‐L1, which inhibits T cell receptor signaling, CCR9 regulates STAT signaling in T cells, resulting in reduced T‐helper‐1 cytokine secretion and reduced cytotoxic capacity. Moreover, inhibition of CCR9 expression on tumor cells facilitated the immunotherapy of human tumors by tumor‐specific T cells in vivo (Khandelwal et al, 2015).…”