The tumor immune microenvironment is emerging as a critical player in predicting cancer prognosis and response to therapies. However, the prognostic value of tumor-infiltrating immune cells in Gingivo-Buccal Oral Squamous Cell Carcinoma (GBOSCC) and their association with tumor size or lymph node metastases status require further elucidation. To study the relationship of tumor-infiltrating immune cells with tumor size (T stage) and lymph node metastases (N stages), we analyzed the density of tumor-infiltrating immune cells in archived, whole tumor resections from 94 patients. We characterized these sections by immune-histochemistry using 12 markers and enumerated tumor-infiltrating immune cells at the invasive margins (IM) and centers of tumors (CT). We observed that a higher density of CD3+ cells in the IM and CT was associated with smaller tumor size (T1-T2 stage). Fewer CD3+ cells was associated with larger tumor size (T3-T4 stage). High infiltration of CD3+and CD8+ cells in IM and CT as well as high CD4+ cell infiltrates in the IM was significantly associated with the absence of lymph node metastases. High infiltrates of CD3+ and CD8+ cells in CT was associated with significantly improved survival. Our results illustrate that the densities and spatial distribution of CD3+ and CD8+ cell infiltrates in primary GBOSCC tumors is predictive of disease progression and survival. Based on our findings, we recommend incorporating immune cell quantification in the TNM classification and routine histopathology reporting of GBOSCC. Immune cell quantification in CT and IM may help predict the efficacy of future therapies.
Several
toll-like receptors (TLRs) reside inside endosomes of specific
immune cellsamong them, aberrant activation of TLR7 and TLR9
is implicated in myriad contexts of autoimmune diseases, making them
promising therapeutic targets. However, small-molecule TLR7 and TLR9
antagonists are not yet available for clinical use. We illustrate
here the importance of C2, C6, and N9 substitutions in the purine
scaffold for antagonism to TLR7 and TLR9 through structure–activity
relationship studies using cellular reporter assays and functional
studies on primary human immune cells. Further in vitro and in vivo pharmacokinetic studies identified
an orally bioavailable lead compound 29, with IC50 values of 0.08 and 2.66 μM against TLR9 and TLR7,
respectively. Isothermal titration calorimetry excluded direct TLR
ligand–antagonist interactions. In vivo antagonism
efficacy against mouse TLR9 and therapeutic efficacy in a preclinical
murine model of psoriasis highlighted the potential of compound 29 as a therapeutic candidate in relevant autoimmune contexts.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.