NF- B Hyperactivation in Tumor Tissues Allows Tumor-Selective Reprogramming of the Chemokine Microenvironment to Enhance the Recruitment of Cytolytic T Effector Cells

Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Cancer Research (Impact Factor: 9.33). 05/2012; 72(15):3735-43. DOI: 10.1158/0008-5472.CAN-11-4136
Source: PubMed


Tumor infiltration with effector CD8(+) T cells (T(eff)) predicts longer recurrence-free survival in many types of human cancer, illustrating the broad significance of T(eff) for effective immunosurveillance. Colorectal tumors with reduced accumulation of T(eff) express low levels of T(eff)-attracting chemokines such as CXCL10/IP10 and CCL5/RANTES. In this study, we investigated the feasibility of enhancing tumor production of T(eff)-attracting chemokines as a cancer therapeutic strategy using a tissue explant culture system to analyze chemokine induction in intact tumor tissues. In different tumor explants, we observed highly heterogeneous responses to IFNα or poly-I:C (a TLR3 ligand) when they were applied individually. In contrast, a combination of IFNα and poly-I:C uniformly enhanced the production of CXCL10 and CCL5 in all tumor lesions. Moreover, these effects could be optimized by the further addition of COX inhibitors. Applying this triple combination also uniformly suppressed the production of CCL22/MDC, a chemokine associated with infiltration of T regulatory cells (T(reg)). The T(eff)-enhancing effects of this treatment occurred selectively in tumor tissues, as compared with tissues derived from tumor margins. These effects relied on the increased propensity of tumor-associated cells (mostly fibroblasts and infiltrating inflammatory cells) to hyperactivate NF-κB and produce T(eff)-attracting chemokines in response to treatment, resulting in an enhanced ability of the treated tumors to attract T(eff) cells and reduced ability to attract T(reg) cells. Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance T(eff) entry into colon tumors.

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    • "It is well established that the CXCR3/CXCL10 chemotactic axis is key to trafficking and differentiation of effector Th1 CD4 þ cells, NK and CD8 þ cells within inflamed tissues (Groom and Luster, 2011; Groom et al, 2012). Furthermore, increased levels of CXCL10 and CCL5/RANTES are associated with enhanced CD8 þ T cell infiltration in melanoma, colorectal and gastric cancers (Ohtani et al, 2009; Kunz et al, 1999;, Muthuswamy et al, 2012). Our findings are consistent with recent studies of the immune microenvironment in breast cancer, where a similar trend of decreased CXCL10 and STAT1 expression was associated with relapse (Ascierto et al, 2012). "
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    ABSTRACT: Background: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype. Methods: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform. Results: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models. Conclusions: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.
    Full-text · Article · Mar 2015 · British Journal of Cancer
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    • "Our finding that the TME of all CRC tumours tested (n ¼ 50) potently suppressed IL-12p70 secretion may also help explain why often DC vaccines that are capable of inducing T-cell responses in vitro may fail in vivo (Rossowska et al, 2009). Local activation of NF-kB and resultant inflammatory cytokines are of great importance in the shaping of the local tumour environment (Muthuswamy et al, 2012). We screened the TME of both metastatic and non-metastatic tumours to determine if there were different patterns of local inflammation and found high levels of inflammatory mediators, notably IL-6 and IL-8, in all the samples. "
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    ABSTRACT: Background Tumour microenvironment (TME) of advanced colorectal cancer (CRC) suppresses dendritic cell (DC) maturation. Here, our aim was to determine how the microenvironment of early-stage tumours influences DCs.Methods:Tumour-conditioned media (TCM) was generated by culturing explant tumour tissue in vitro (n=50). Monocyte-derived DCs (MDDCs) of healthy donors or cancer patients were pretreated with TCM and stimulated with lipopolysaccharide (LPS). DC maturation was assessed by flow cytometry and cytokine production measured by ELISA.Results:TCM from both early- and late-staged tumours abrogated LPS-induction of IL-12p70 secretion, while increasing IL-10. The profile of inflammatory mediators in TCM was similar across stages, and all increased pSTAT3 expression by DCs.CRC patient DCs (n=31) secreted low levels of IL-12p70 and failed to upregulate expression of maturation markers in response to LPS. Furthermore, in vitro culture of autologous DCs with TCM did not change the hypo-responsiveness of patient DCs.Conclusion:Our data demonstrates that the TME of all stages of CRC contains inflammatory mediators capable of suppressing local DCs. MDDCs obtained from CRC patients are hyporesponsive to stimuli such as LPS. Measures to reverse the negative influence of the TME on DCs will optimise cancer vaccines in both early- and late-stage CRC.British Journal of Cancer advance online publication, 24 July 2014; doi:10.1038/bjc.2014.367
    Full-text · Article · Jul 2014 · British Journal of Cancer
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    • "In a mouse model, increased expression of ligands for CXCR3, CXCL9, and CXCL10 can elicit antitumor response accompanied with an enhanced infiltration of CD4+ and CD8+ lymphocytes [26]. Consistently with this observation, in human gastric and colorectal cancer, TILs express CXCR3 (Figure 2) [27–29]. Moreover, high levels of CXCL9 and CXCL10 are produced by stromal cells, mainly macrophages [28]. "
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    ABSTRACT: Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer.
    Full-text · Article · May 2014 · Mediators of Inflammation
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