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Biomarkers for the Immune Checkpoint Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Weijie Ma, Sixi Wei, Eddie C. Tian, Tianhong Li
Antitumor T cells recognize not only tumor-specific mutant peptides like neoantigens, but also cancer germline antigens (CGAs), germline proteins whose expression is typically restricted to germline cells but is upregulated in tumor cells. Tumor types harboring higher numbers of nonsynonymous somatic variants have higher response rates to immunotherapy, due to greater numbers of neoantigens [28]. In some cases of MMR deficiency, whole-exome sequencing confirmed a 20-fold-higher level of nonsynonymous mutation-associated neoantigen load compared to MMR-proficient patients; this is consistent with other reports demonstrating an association between higher mutational load and response to anti-PD-1 in NSCLC [27]. In one example, a patient with metastatic lung adenocarcinoma showed an exceptional response to atezolizumab (anti-PD-L1). Whole-exome sequencing of the patient’s tumor and blood revealedgain-of-function somatic alterations in Janus kinase 3 (JAK3) as well as germline mutations in the same allele [78]. These studies demonstrate the impact of germline mutations that can influence neoantigen formation or immune signaling and may serve as future predictors of sensitivity to immunotherapy.
Newer Agents in Systemic Treatment
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Rachita Dhurat, Shilpi Agarwal
Currently, four important members of the JAK family are known. Janus kinase 1 and Janus kinase 2 are involved in host defense, hematopoiesis, neural development, and growth. Janus kinase 3 and tyrosine kinase 2 have a role in the immune response [32].
Appendiceal Cancer
Published in Dongyou Liu, Tumors and Cancers, 2017
Appendiceal cancer is linked to mutations in the APC, ATM, KRAS, IDH1, NRAS, PIK3CA, SMAD4, and TP53 genes. Specifically, GCC demonstrates loss in chromosomes 11q, 16q, and 18q, in addition to strong carcinoembryonic antigen, caudal-type homeobox transcription factor 2, cytokeratin 7 (CK7), CK20 expression (an epithelial element not present in classic carcinoids), and transcription factor Math-1 and HD5 expression. MAC and LAMN contain mutations in the KRAS, GNAS, and TP53 genes; losses of SMAD4 protein expression (and loss of heterozygosity at chromosome 18q); and p53 overexpression. In addition to alterations in KRAS, GNAS, and TP53 genes, mucocele harbors mutations in JAK3 (Janus kinase 3), AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC, MET (met proto-oncogene), PIK3CA, RB1 (retinoblastoma 1), and STK11 (serine/threonine kinase 11) genes; whereas PMP has mutation in the RB1 gene [3].
JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys
Published in Islets, 2019
Jong-Min Kim, Jun-Seop Shin, Byoung-Hoon Min, Seong-Jun Kang, Il-Hee Yoon, Hyunwoo Chung, Jiyeon Kim, Eung-Soo Hwang, Jongwon Ha, Chung-Gyu Park
Recently, significant attention has been paid to develop Janus kinase 3 (JAK3) inhibitor as a novel immunosuppressive drug in organ transplantation, because this class of inhibitor can be theoretically appealing for several reasons.9 First, the mutation in the gene encoding JAK3, a cytoplasmic tyrosine kinase resulted in a phenotype similar to X-linked severe-combined immunodeficiency disease (X-SCID), which is characterized by immune deficiency such as T−B+NK− cell phenotype. Second, JAK3 has a more restricted expression pattern than other JAKs such that it is expressed at high levels in immune cells. Third, JAK3 is tightly associated with the cytokine receptor subunit, common γ chain, which is important for signal transduction of many cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Thus, JAK3 inhibitor would inhibit the function of T cells, B cells, NK cells, memory T cells through IL-2, IL-4, IL7, IL-15 signaling pathway, respectively. Consistent with this notion, Busque et al. recently reported that long-term tofacitinib was effective in preventing renal allograft acute rejection and preserving renal function in open-label, long-term extension (LTE) study.10 All these features led us to hypothesize that JAK3 inhibitor may replace tacrolimus in immunosuppressive regimen in allogeneic islet transplantation setting. To test this hypothesis, clinically available JAK3 inhibitor, tofacitinib, was used in replacement with tacrolimus in CIT07 immunosuppressive regimen in cynomolgus monkey allogeneic islet transplantation model.
Transient leukemia of Down syndrome
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Valentina Sas, Cristina Blag, Gabriela Zaharie, Emil Puscas, Cosmin Lisencu, Nicolae Andronic-Gorcea, Sergiu Pasca, Bobe Petrushev, Irina Chis, Mirela Marian, Delia Dima, Patric Teodorescu, Sabina Iluta, Mihnea Zdrenghea, Ioana Berindan-Neagoe, Gheorghe Popa, Sorin Man, Anca Colita, Cristina Stefan, Seiji Kojima, Ciprian Tomuleasa
Kiyoi et al. have shown that mutations of the Janus kinase 3 (JNK3) gene were also reported in TL-DS blasts, results also shown by [110,111]. JAK3 mutations are very early events that can cooperate with GATA1 mutations during the development of TL-DS [112]. The fact that JAK3 mutations occurred in patients with TL-DS and in patients with DS-AMkL only at a low frequency suggests that other distinct genetic changes probably contribute to the development of TL-DS and to the progression to AMkL from TL-DS. JAK3 activating mutations provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on AMkL and TL-DS patients carrying activating JAK3 mutations [113]. Mutations in JAK1, JAK2, JAK3, MPL, or SH2B3 (LNK) were found in 35% of DS-AMkL cases but rarely in TL-DS and non-DS-AMkL by Yoshida et al. [97,114]. De Vita et al. reported an acquired loss-of-function JAK3 mutation due to a large deletion (592 bp) of a fragment encoding the JH1 kinase domain. This mutation was found in two of eight patients with TL-DS and in one of eight patients with DS-AMkL [92,115,116].
Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates
Published in Gut Microbes, 2018
Tasha Barr, Suhas Sureshchandra, Paul Ruegger, Jingfei Zhang, Wenxiu Ma, James Borneman, Kathleen Grant, Ilhem Messaoudi
In the colon, 3 genes were upregulated and 108 genes were downregulated with ethanol-consumption (Fig. 3A). Of the 107 downregulated DEG with human homologs (Fig. 3B), 67 enriched to the GO term “immune system process” (Fig. 3C and E) and 71 enriched to the disease term “immune system diseases” (Fig. 3D). These genes include B-cell markers (CD19, CD72, CD79B); co-stimulatory markers (CD83); as well as cytokines, chemokines, and their receptors (e.g. IL24, CCL19, IL21R, and CCR7). Several DEG also encode for T-cell markers (e.g. CD1C, CD2, CD3D, CD3E, CD5, CD8A) and enriched to GO terms “regulation of T-cell activation” and “T-cell differentiation”. Interestingly, several of these DEG were upregulated with ethanol consumption in the ileum (CD1C, CD19, CD22, CD72, CD79B, CCL19, CCR7, CXCR4, FCRL1, IL21R, TNFRSF13C). Additional downregulated immune genes include indoleamine-2,3-dioxygenase-1 (IDO1), which drives differentiation of regulatory T-cells; peptidase inhibitor (PI3); and defensin-6 (DEF6). Some downregulated genes are also critical for signal transduction including Janus kinase-3 (JAK3) and signal transducer and activator of transcription (STAT1). Several of the immune genes listed above enriched to the disease term “gastrointestinal neoplasms” and are also associated with CRC development including the T cell chemoattractant CXCL9, keratin-7 (KRT7), and IDO1.