Tumor development and therapeutic resistance are linked with tumor-associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration in tumors via chemokine axis. Chemokine expression, which determines the pro or anti-inflammatory status of myeloid cells, are partly regulated by the nuclear factor-kappa B (NF-κB) pathway. Here, we identified that conditional deletion of canonical NF-κB signaling (p65) in myeloid cells inhibited syngeneic glioblastoma (GBM) through decreased CD45 infiltration in tumors, as characterized by decreased TAMs (CD206+) and MDSCs (Gr1+ CD11b+), increased dendritic cells (CD86+) and cytotoxic T cells (CD8+) in the p65 knockout (KO) mice. Proinflammatory cytokines (IFNγ, MCP1, MIP1α, and TNFα) and myeloid differentiation factor (Endoglin) were increased in myeloid cells from p65 KO tumor, which demonstrated an influence on CD8+T cell proliferation. In contrast, p65KO athymic chimeric mice with human GBM, failed to inhibit tumor growth, confirming the contribution of T cells in an immune competent model. The analysis of human datasets and GBM tumors revealed higher expression of p65 in GBM-associated CD68+ macrophages compared to neighboring stroma. Thus, canonical NF-κB signaling has an anti-inflammatory role and is required for macrophage polarization, immune suppression, and GBM growth. Combining an NF-κB inhibitor with standard therapy could improve antitumor immunity in GBM.

Experimental or traumatic nerve injury causes the degeneration of associated taste buds. Unlike most sensory systems, the sectioned nerve and associated taste buds can then regenerate, restoring neural responses to tastants. It was previously unknown whether injury-induced immune factors mediate this process. The proinflammatory cytokines, interleukin (IL)-1α and IL-1β, and their requisite receptor are strongly expressed by anterior taste buds innervated by the chorda tympani (CT) nerve. We tested taste bud regeneration and functional recovery in mice lacking the IL-1 receptor. After axotomy, the chorda tympani nerve (CT) nerve regenerated but was initially unresponsive to tastants in both wild-type (WT) andIl1r KOmice. In the absence ofIl1rsignaling, however, neural taste responses remained minimal even >8 weeks after injury in both male and female mice while normal taste function recovered by 3 weeks in WT mice. Failed recovery was due to a 57.8% decrease in regenerated taste buds inIl1rKO compared to WT axotomized mice.Il1agene expression was chronically dysregulated, and the subset of regenerated taste buds were reinnervated more slowly and never reached full volume as progenitor cell proliferation lagged in KO mice.Il1rsignaling is thus required for complete taste bud regeneration and the recovery of normal taste transmission, likely by impairing taste progenitor cell proliferation. This is the first identification of a cytokine response that promotes taste recovery. The remarkable plasticity of the taste system makes it ideal for identifying injury-induced mechanisms mediating successful regeneration and recovery.Significance Statement.Taste plays a critical role in nutrition and quality of life. The adult taste system is highly plastic and able to regenerate following the disappearance of most taste buds after experimental nerve injury. Several growth factors needed for taste bud regeneration have been identified, but we demonstrate the first cytokine pathway required for the recovery of taste function. In the absence of IL-1 cytokine signaling, taste bud regeneration is incomplete preventing the transmission of taste activity to the brain. These results open a new direction in revealing injury-specific mechanisms that could be harnessed to promote the recovery of taste perception after trauma or disease.

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Benign prostatic hyperplasia (BPH), a non-malignant proliferative disease of the prostate, has a global incidence of over 210 million men aged 50 years or older. BPH is essentially a non-cancerous (non-malignant tumor) with significant morbidity. The severity varies from mild urinary retention to severe lower urinary tract symptoms (LUTS) accounting for greater than 50% of hospital visits for difficulty with urination, retention, and pain, and close to 40% of the prostate surgeries. BPH strongly associates with prostate volume that begins to increase in men aged 40 or higher. We investigated the role of chemokine and chemokine receptors in three immortalized cell lines and primary cultures derived from fresh BPH tissue following transurethral resection of the prostate. We analyzed the levels of chemokines and chemokine receptors secreted in the culture medium and in the mRNA from cells by qPCR, western blotting and Cytokine arrays. The epithelial identity of primary cultures was established by analyzing cytokeratin expression. Two natural products isolated from Allspice were identified that inhibit the growth of BPH cultures. A cell line identified as the BPH progenitor, a BPH intermediary cell line and a cell line with frank BPH features secreted a large excess of chemokine, predominantly CXCL-VIII or Interleukin-8 (IL-8). Unusually high amount of IL-8 was secreted by BPH progenitor cells and intermediate cells as compared to a stable normal prostate cell line (RWPE1) derived from the peripheral zone of the prostate, which did not secrete any IL-8 or express its receptor. The investigation found that expression of CXC receptors CXCR1, CXCR2 and an IL-8 inducible CXCR (CXCR7) was absent in progenitor cells and in intermediate cells, but was highly expressed in the cell line derived from BPH tissue and more significantly, in primary cultures of BPH tissue. Further, primary cultures and progenitor cells expressed high levels of immune stimulatory factors indicating PMN and monocyte infiltration leading to potential chronic inflammation of the transitional zone of the prostate. The natural products from Allspice inhibited all members of the IL-8 axis and proliferation, suggesting their potential preventative potential for BPH. These results demonstrate how a novel chemokine axis is likely to enhance pathogenesis of BPH and suggest several avenues to control the abnormal growth of prostate in aging male. Note: This abstract was not presented at the meeting. Citation Format: Diandra K. Smith, Natasha Venugopal, Martha K. Terris, Bal L. Lokeshwar. The critical role of interleukin-8 chemokine axis in the development of benign prostatic hyperplasia (BPH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 123A.