In the tumor microenvironment (TME), cancerous cells, together with
stromal and immune cells are organized within a specific extracellular
matrix (ECM) that provides cues orchestrating cell behaviour. Therapies
which harness our inherent ability to destroy tumors, such as antibodies
that activate cytotoxic lymphocytes (CTL) to re-engage tumor cell killing
(immune checkpoint therapy, ICT), are successful in treating some but not
all cancer patients. Emerging evidence suggests a key role of the ECM in
regulating the crosstalk between cancer and immune cells. Therefore, a
more complete understanding of how cells and the ECM in the TME interact
will be important to design new and complementary approaches to treat
cancer. We propose a signaling axis comprising ECM and CXCR4, involving
tenascin-C (TNC), hyaluronan (HA), CXCL12 and CD44, to modulate tumor
immunity thereby compromising ICT. We aim at understanding how CXCR4
signaling complexes form and how this impacts CTL behaviour by using
proteomics, in vivo targeting and computational modelling. As CXCR4 plays
an important role in CTL reactivation, more insight about its regulation in
space and time may provide novel information with therapeutic potential
for improving ICT.