Abstract
Simple SummaryThis study provides a conceptual overview correlating temporal changes in the tumor immune-microenvironment (TIME) to the non-ablative pulse focused ultrasound (pFUS) in two different types of tumors. The pFUS-induced immunomodulation revealed differential anti-tumor molecular and cellular responses between the two tumor types, demonstrating tumor-type-dependent responses to identical pFUS sonication parameters. It also supports the potential use of pFUS as a possible adjuvant to ablative tumor treatment to elicit enhanced anti-tumor responses and slow tumor growth.Focused ultrasound (FUS) has shown promise as a non-invasive treatment modality for solid malignancies. FUS targeting to tumors has been shown to initiate pro-inflammatory immune responses within the tumor microenvironment. Pulsed FUS (pFUS) can alter the expression of cytokines, chemokines, trophic factors, cell adhesion molecules, and immune cell phenotypes within tissues. Here, we investigated the molecular and immune cell effects of pFUS on murine B16 melanoma and 4T1 breast cancer flank tumors. Temporal changes following sonication were evaluated by proteomics, RNA-seq, flow-cytometry, and histological analyses. Proteomic profiling revealed molecular changes occurring over 24 h post-pFUS that were consistent with a shift toward inflamed tumor microenvironment. Over 5 days post-pFUS, tumor growth rates were significantly decreased while flow cytometric analysis revealed differences in the temporal migration of immune cells. Transcriptomic analyses following sonication identified differences in gene expression patterns between the two tumor types. Histological analyses further demonstrated reduction of proliferation marker, Ki-67 in 4T1, but not in B16 tumors, and activated cleaved-caspase 3 for apoptosis remained elevated up to 3 days post-pFUS in both tumor types. This study revealed diverse biological mechanisms following pFUS treatment and supports its use as a possible adjuvant to ablative tumor treatment to elicit enhanced anti-tumor responses and slow tumor growth.
Highlights
IntroductionSolid tumors are a dynamic compilation of malignant cells, stem cells along with infiltrating immune cells, vasculature, stroma, extracellular matrix, and soluble factors that
Solid tumors are a dynamic compilation of malignant cells, stem cells along with infiltrating immune cells, vasculature, stroma, extracellular matrix, and soluble factors that 4.0/).together constitute the tumor microenvironment [1,2,3]
We investigated the temporal changes following non-ablative Pulsed FUS (pFUS) on CCTF, cell adhesion molecules (CAM), immune cell profiles, and transcriptomics of murine B16 melanoma and 4T1 breast cancer flank tumors, along with immune cell changes in spleens (Sp) and inguinal lymph nodes (LN) up to 5 days post-sonication compared to un-sonicated time-matched controls (TMC)
Summary
Solid tumors are a dynamic compilation of malignant cells, stem cells along with infiltrating immune cells, vasculature, stroma, extracellular matrix, and soluble factors that. The tumor immune microenvironment (TIME) reflects interactions between tumor cells and the immune system, which are mediated by damage-associated molecular patterns (DAMP); cytokines, chemokines, and trophic factors (CCTF); and cell adhesion molecules (CAM) [1]. Together, they regulate tumor growth, metastatic dissemination, and therapeutic outcomes [4,5]. We previously demonstrated pFUS to modulate immune cell phenotypes, CCTF, and CAM expression in B16 and 4T1 flank tumors at 24 h [25,26] In both tumor types, TIME shifted from I-E towards I-I following pFUS and was associated with slowing of tumor growth. The temporal dynamics of TIME following pFUS revealed differential anti-tumor molecular and cellular responses between the two tumor types, demonstrating tumor-type-dependent responses to identical pFUS sonication parameters
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