Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [

Purpose p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. Interleukin-27 (IL-27) is an important immunomodulatory cytokine but its impact on mutant p53-driven tumorigenesis has not been reported. Experimental Design IL27RA−/− mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA−/−p53H/+ and IL27RA−/−p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via immunohistochemistry and western blot. Results this study unraveled that lack of IL-27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL-27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL-27 signaling is closely associated with increased mutant p53 stability in vivo from early age. Conclusions These results suggest that IL-27 signaling modulates the oncogenic properties of mutant p53 in vivo.

The susceptibility of African American recipients to acute rejection and to DGF was not confirmed to be associated with DARC alleles or genotype. Future studies should exclude a potential role of donor-related DARC in transplant outcomes.

Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b−/− mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin—a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.

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Although the genetic components that drive carcinogenesis and the stem cell involvement in cancer initiation have been established, the mechanism through which the immune response/cytokine milieu within the tumor microenvironment promotes cancer formation and stem cell behavior is an exciting yet understudied area of research. This statement is specifically true with an important regulator of the immune response, IL27, which is known to have both pro- and anti-inflammatory properties. During an inflammatory response, IL27 has been shown to regulate two canonical cytokines IL10 and IL17, and to affect multiple inflammatory and infectious diseases. Yet, the function of IL27 at physiological levels during the instigation of carcinogenesis remains unknown. To determine the role of IL27 during the early stages of cancer formation, the well-established two step skin carcinogenesis model (DMBA followed by the promoter benzoyl peroxide (BP)) was used. Interestingly, mice that lack IL27 signaling (IL27RA-/-) are protected during the initiation of carcinogenesis as they have lower incidence of papilloma formation over time when compared to wildtype mice. Additionally, wildtype mice treated with IL27 via gene therapy have a higher incidence and develop more papillomas when compared to control counterparts. Bone marrow transfer studies showed that IL27 signaling in both hematopoietic and non-hematopoietic cells is needed to drive skin carcinogenesis. Additionally, IL27 signaling induces loss of epithelial stem cell homeostasis/maintenance. In mice treated with DMBA/BP, 23% of the wildtype mice treated had ulcerations that failed to heal over time, while none of IL27RA-/- showed any defects in the skin. In mice that went under bone marrow transfer followed by DMBA/BP, 40% of wildtype ones developed severe skin ulcerations, while none of the IL27RA-/- developed any skin abnormalities. And lastly, mice undergoing the tumorigenesis protocol that were treated with IL27 developed hair loss, which was mirrored by loss of hair follicles. These phenotypes are like due to the loss of epithelial stem cell maintenance and/or homeostasis by IL27. These finding propose an unrecognized role of IL27 in promoting papilloma formation and disrupting epithelial cell maintenance and/or homeostasis. Citation Format: Denada Dibra, Melissa Newman, Jeffry Cutrera, Shulin Li. The role of IL27 as a driver of skin carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1430. doi:10.1158/1538-7445.AM2013-1430

Ras activation plays an important role in Squamous Cell Carcinomas (SCC) development. Additionally, there is large evidence confirming the role of inflammation during cancer initiation. However, the interaction between inflammation and oncogene activation is poorly understood in tumorigenesis. We found that IL27 promotes papilloma formation in a 2 step skin carcinogenesis (DMBA followed by benzoyl peroxide) model where DMBA causes Ras mutation. Because K15-positive follicular stem cells contribute to papillomas in the two-step skin carcinogenesis model, we used an inducible oncogenic K-RasG12D under the K15 promoter, which marks follicular stem cells. Indeed, treating mice with IL27 increased papilloma incidence earlier in these K15-K-RASG12D mice. Mechanistically, we see that ETAR+ macrophages are significantly increased in IL27-treated K15-K-RasG12D mice. Additionally, the ETAR ligand ET1, and the downstream factor of ETAR, COX2, are upregulated in these K15-KRasG12D mice by IL27, suggesting that ET1/ETAR pathway is involved in IL27 mediated papilloma formation. Indeed, IL27-mediated papilloma formation was reversed by using the ETAR inhibitor ZD4054. Therefore, the data shown here suggest that IL27 drives accumulation of ETAR+ macrophages, ET1, and Cox-2 in the skin and ultimately causes faster papilloma formation in K-Ras mutated follicular stem cells. These findings propose an unrecognized role of IL27 during initiation of skin carcinogenesis. Citation Format: Denada Dibra, Xueqing Xia, Melissa Newman, Camille Keenan, Shulin Li. IL27 promotes papilloma formation via inducing a pro-inflammatory milieu in the skin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1082. doi:10.1158/1538-7445.AM2014-1082