Abstract 4615: Measurement of systemic inflammatory responses in mouse syngeneic tumor models
Authors: Solban Nicolas , Linn Douglas , Li Cai , Cristescu Razvan , Long Brian J. 
Published: August 2019

Abstract
Identifying valid biomarkers that predict for durable responses and benefit from treatment has long been the subject of intense investigation. Following the immense success of cancer immuno-therapies at stimulating anti-tumor immune responses in a subset of patients, a further understanding of systemic inflammatory responses (readily obtained from serum) to predict outcome is urgently needed. Multiple studies have shown that an elevated neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with decreased overall survival and decreased disease-free survival. We evaluated hematology parameters in mice following inoculation with various mouse tumor cell lines in order to determine if any systemic markers of inflammation could predict for tumor progression. Eleven murine cell lines were individually inoculated subcutaneously in C57BL/6 mice (MC38, B16F10, TC-1, and LL/2 cell lines), BALB/c mice (4T1, CT26, Renca, and EMT-6 cell lines), DBA/2 mice (CM-3 cell line), and CH3 mice (MBT-2 cell line). Animals were euthanized when tumors reached pre-determined sizes (100 mm3, 250 mm3, 500 mm3, 1000 mm3, and 1500 mm3), blood was collect for hematology, and tumors were fixed for histology. The 4T1 cells were also used to establish a metastasis model. Briefly, 4T1 primary subcutaneous tumors are removed 14 days post-inoculation to allow metastasis to develop. On day 4, 11, and 18 following resection, 50 μL of blood was collected for longitudinal hematology measurements. Hematology parameters varied between healthy mice strains. A significant increase in white blood cells (WBC) was measured in DBA/2 mice compared to other strains and a significant decrease in monocytes was measured in C57BL/6 mice compared to other strains. Nonetheless, NLR was strongly correlated with tumor weights across all of the models, with the larger tumors having the highest NLR. On the other hand, NLR did not correlate with body weight loss, suggesting an independent effect from other prognostic factors like cachexia. Overall, NLR was highest in the 4T1 models (subcutaneous and metastatic), consistent with human data where NLR increases with disease stage. Models were also classified based on response to anti-PD-1 treatment. Unresponsive models, 4T1, EMT-6, TC-1 LL/2 had a higher NLR compared to the responsive models (MC38, CM3, and MBT-2). In conclusion, this survey of hematology parameters following mouse cell line inoculation showed a strong correlation of neutrophils, NLR, and lymphocytes with tumor burden. Furthermore, models responsive to immuno-therapies had lowest NLR, similar to observations in humans. This survey could be helpful in modeling clinical responses and potentially identifying novel tumor factors that modulate systemic inflammation.
Citation Format: Nicolas Solban, Douglas Linn, Cai Li, Razvan Cristescu, Brian J. Long. Measurement of systemic inflammatory responses in mouse syngeneic tumor models [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 4615.