Abstract
Immune checkpoint therapy, where CD8 tumor infiltrating T lymphocytes (TIL) are reactivated, is a promising anti‐cancer treatment approach, yet with low response rates. The extracellular matrix, in particular tenascin‐C, may generate barriers for TIL. To investigate this possibility, we used a MMTV‐NeuNT and syngeneic mammary gland grafting model derived thereof with engineered tenascin‐C levels and observed accumulation of CD8 TIL in tenascin‐C‐rich stroma. Inhibition studies revealed that tenascin‐C induced CXCL12 through TLR4. By binding CXCL12, tenascin‐C retained CD8 TIL in the stroma. Blockade of CXCR4, the receptor of CXCL12, enhanced macrophage and CD8 TIL infiltration and reduced tumor growth and subsequent metastasis. Retention of CD8 TIL by tenascin‐C/CXCL12 was also observed in human breast cancer by tissue staining. Moreover, whereas high CD8 TIL numbers correlated with longer metastasis‐free survival, this was not the case when also tenascin‐C and CXCL12 levels were high. Altogether, these results may be useful for improving tumor immunity as diagnostic tool and to formulate a future “TIL‐matrix‐release‐and‐reactivate” strategy.
Highlights
Immune checkpoint therapy (ICT) is a promising approach to activate the body’s immune system to fight cancer
The TNC protein binds CXCL12 generating a substratum that tethers CD8 TIL in the stroma preventing infiltration of CD8 TIL into the tumor nests and subsequent tumor cell killing. This mechanism could be relevant in human breast cancer as patients with tumors of high TNC expression show high CD8 TIL in the (TNC-rich) stroma which correlates with shorter metastasis-free survival (MFS). (Lower left) Upon removal of TNC anti-tumor immunity is activated and characterized by lower CXCL12 expression, higher CD8 TIL nest infiltration, and a reduced metastasis rate as previously shown (Sun et al, 2019)
Low TNC and high CD8 TIL correlate with longest MFS. (Lower right) TNC impacts CD8 TIL through CXCL12/CXCR4
Summary
Immune checkpoint therapy (ICT) is a promising approach to activate the body’s immune system to fight cancer. Inactive CD8 TIL can get reactivated with antibodies targeting PD1, PD-L1, or CTLA (Duraiswamy et al, 2013; Huang et al, 2017); CD8 TIL are often either scarce or located inside the tumor stroma not reaching the tumor cells (Joyce & Fearon, 2015). The so-called “immunoscore” takes into account the exclusion of CD8 TIL from tumor cell clusters (Galon & Bruni, 2019) which are often organized as nests surrounded by stroma, that is rich in extracellular matrix (ECM) (Pickup et al, 2014; Spenle et al, 2015). The roles of the ECM in controlling CD8 TIL infiltration are not well understood (Erdag et al, 2012; Galon et al, 2012; Joyce & Fearon, 2015)
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