Adaptive counter strike mechanism of the immune system

Baseline T cell location and density in metastatic melanomas have predictive value in the treatment outcome of patients receiving Immunotherapy. Using a modified Boyden chambers, here we show that the melanoma–T cell interactions lead to an increase in the number of T cells that migrate toward melanoma cells. This interaction is both HLA I and IFNγ dependent as was demonstrated using β2M KD, JAK1 inhibitors and IFNgR1 blocking antibodies. Indeed, all three experiments eliminated the migratory effect. Co-cultures using T cells and melanoma cells demonstrate an induction of the inducible isoform of ADAR1. This was visualized in-situ using dynamic cell blocks as well as observed with western blots. Moreover, experimental silencing or overexpression of ADAR1 decreases or increases, respectively, specific T cell migration toward melanoma cells. Indeed, chemokine arrays demonstrate that ADAR1 significantly alters the secretion levels of multiple chemokines from melanoma cells. Collectively, ADAR1 downregulation facilitates a pro-tumor environment by limiting the amount of T-cells that migrate to the area hence creating a cold tumor. On the other hand, antigen-specific T-cells forces an adaptive counter attack by eliciting a positive feedback loop through ADAR1 induction in the surviving tumor cells, which in turn induces the expression of several chemokines and thereby increasing the chemotactic potential and influx of new T cells.