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Fig. 3 | Molecular Cancer

Fig. 3

From: Mechanisms of rapid cancer cell reprogramming initiated by targeted receptor tyrosine kinase inhibitors and inherent therapeutic vulnerabilities

Fig. 3

Rapid transcriptional changes in response to oncogenic RTK inhibition may function in a non-cell autonomous manner. Targeted RTK inhibitors stimulate rapid transcriptional induction of TGFβ2, IL6, and a type I IFN program that includes the chemokines, CXCL9 and CXCL10. As shown, these rapidly induced secreted factors are proposed to signal in a paracrine manner to the TME including cancer associated fibroblasts (CAFs) and pro-tumorigenic and anti-tumorigenic cell types of the immune microenvironment. IL6 and TGFβ2 act on the TME to inhibit the activity of CD8+ T cells and increase the recruitment of pro-tumor immune cells including M2-type macrophages and granulocytic myeloid-derived suppressor cells (MDSCs). Additionally, cytokines can increase the activation of CAFs in the TME to increase tumorigenesis. By contrast, the type I IFN response genes, CXCL9 and CXCL10, lead to recruitment of specific T cells and natural killer (NK) cell populations that function in an anti-tumorigenic manner. The balance of these paracrine signals is predicted to contribute to overall tumor growth and survival in the setting of RTK inhibitors, but also to increase vulnerability to distinct immunotherapy strategies

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