Colorectal cancer is a leading cause of cancer related deaths in the U.S., with African-Americans having higher incidence and mortality rates than Caucasian-Americans. Recent studies have demonstrated that anti-tumor cytotoxic T lymphocytes provide protection to patients with colon cancer while patients deficient in these responses have significantly worse prognosis. To determine if differences in cytotoxic immunity might play a role in racial disparities in colorectal cancer 258 microsatellite-stable colon tumors were examined for infiltrating immune biomarkers via immunohistochemistry. Descriptive summary statistics were calculated using two-sample Wilcoxon rank sum tests, while linear regression models with log-transformed data were used to assess differences in race and Pearson and Spearman correlations were used to correlate different biomarkers. The association between different biomarkers was also assessed using linear regression after adjusting for covariates. No significant differences were observed in CD8+ (p = 0.83), CD57+ (p = 0.55), and IL-17-expressing (p = 0.63) cell numbers within the tumor samples tested. When infiltration of granzyme B+ cells was analyzed, however, a significant difference was observed, with African Americans having lower infiltration of cells expressing this cytotoxic marker than Caucasians (p<0.01). Analysis of infiltrating granzyme B+ cells at the invasive borders of the tumor revealed an even greater difference by race (p<0.001). Taken together, the data presented suggest differences in anti-tumor immune cytotoxicity may be a contributing factor in the racial disparities observed in colorectal cancer.
Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer. Graphical abstract: SENTI-101 schematic and mechanism of action SENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.
Retrieval inhibition hypothesis of directed forgetting effects assumed TBF (to-be-forgotten) items were not retrieved intentionally, while selective rehearsal hypothesis assumed the memory representation of retrieved TBF (to-be-forgotten) items was weaker than TBR (to-be-remembered) items. Previous studies indicated that directed forgetting effects of item-cueing method resulted from selective rehearsal at encoding, but the mechanism of retrieval inhibition that affected directed forgetting of TBF (to-be-forgotten) items was not clear. Strategic retrieval is a control process allowing the selective retrieval of target information, which includes retrieval orientation and strategic recollection. Retrieval orientation via the comparison of tasks refers to the specific form of processing resulted by retrieval efforts. Strategic recollection is the type of strategies to recollect studied items for the retrieval success of targets. Using a “directed forgetting” paradigm combined with a memory exclusion task, our investigation of strategic retrieval in directed forgetting assisted to explore how retrieval inhibition played a role on directed forgetting effects. When TBF items were targeted, retrieval orientation showed more positive ERPs to new items, indicating that TBF items demanded more retrieval efforts. The results of strategic recollection indicated that: (a) when TBR items were retrieval targets, late parietal old/new effects were only evoked by TBR items but not TBF items, indicating the retrieval inhibition of TBF items; (b) when TBF items were retrieval targets, the late parietal old/new effect were evoked by both TBR items and TBF items, indicating that strategic retrieval could overcome retrieval inhibition of TBF items. These findings suggested the modulation of strategic retrieval on retrieval inhibition of directed forgetting, supporting that directed forgetting effects were not only caused by selective rehearsal, but also retrieval inhibition.
Background: Colorectal cancer is the second leading cause of cancer deaths in the US. Genetic predisposition occurs in ∼30% of cases, suggesting that treatments with the ability to decrease lesion formation could significantly improve disease-free survival in potential patients with a strong family history. Genetically-engineered bacterial minicells (MC) are noninfectious, nano-sized bacterial particles derived from E. coli that can display immunomodulatory and antitumor activity in animal models of cancer. The expression of Invasin on the MC surface targets them to cancer-associated integrin heterodimers exposed on malignant cells, where they deliver Perfringolysin O, a unique tumorlytic bacterial toxin, that destroys these cells. We hypothesize that these MC can reduce colon lesions in genetically predisposed animals and that they have potential to be developed as a ‘probiotic’ therapy for individuals at high risk to develop colorectal cancer. Methods: The TS4CRE mouse line expresses the Cre recombinase specifically in the distal ileum and colon under the control of the fatty acid binding protein-4 promoter. The Apcfl-468 mouse line has lox-P recombination sites flanking exons 11-12 of the Apc gene. Cross-breeding results in a deletion in one allele of the Apc gene in a tissue-specific manner, resulting in lesion formation by 14-18 weeks of age. Cross-bred mice were treated intra-rectally with 1.5×109 MC or PBS, once a week for 6 doses, at either 8-13 or 14-19 weeks of age and harvested at various times after treatment is complete to evaluate tumor number and size. Tumor and tumor adjacent tissue is evaluated for immune biomarkers using qPCR and immunohistochemistry studies. Mann-Whitney (two-tailed) tests are used to determine statistical significance. Results: MC treatment during lesion development (14-19 weeks of age) significantly decreases tumor number (p = 0.007) and size (p = 0.03) in mice harvested at 6 months of age as compared to controls. Similarly, in animals treated from 8-13 weeks of age, when lesions are absent or only in the earliest stages, a significant decrease in tumor number (p = 0.04) was observed. MC can reduce tumor load through direct killing of developing lesions but they also have the potential to modulate immune responses. Since immune/inflammatory mediators are known to significantly contribute to tumor progression in colorectal cancer, decreased tumors in MC treated mice could be the result, at least in part, of a change in the immune/inflammatory environment of the colon. Chloracetate Esterase (CAE) staining for inflammatory granulocytes and mast cells showed that numbers of CAE+ cells in tumors and normal adjacent tissue from MC treated mice (at 14-19 weeks of age) were significantly lower than PBS-treated controls (p = 0.02). Moreover we saw that cells expressing CD11b, a biomarker for inflammatory, myeloid-lineage cells, were also significantly decreased in MC treated mice (p = 0.01). In addition, using qPCR we have determined that both the CD8 and IFNγ biomarkers were significantly increased in the tumor tissue of MC treated mice (p = 0.03 for each) while perforin and Tbet were increased in the tumor-adjacent tissue in these same mice (p = 0.04 for each), when compared to controls. Conclusions: Taken together, these data strongly suggest that MC reduce colon tumor burden in genetically predisposed mice, most likely both by directly eliminating tumor cells and changing the immune environment of the lesions. The immunomodulatory effects appear to consist of both increased anti-tumor immunity and decreased inflammatory cell infiltration. Future studies will continue to access the actions of these MC and the possibility that they can be developed as a ‘probiotic’ therapeutic approach against colorectal cancer in genetically predisposed individuals. Citation Format: Mengxi Tian, Mohammad W. Khan, Shea Grenier, Shingo Tsuji, Matthew A. Giacalone, Kathleen L. McGuire. Bacterial minicells decrease tumor development and modulate immunity in a mouse mouse model of colon cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B017.
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