Reduced tumor‐antigen density leads to PD‐1/PD‐L1‐mediated impairment of partially exhausted CD8⁺ T cells

Abstract

Clinical progression of cancer patients is often observed despite the presence of tumorreactive T cells. Co-inhibitory ligands of the B7 superfamily have been postulated to play a part in this tumor-immune escape. One of these molecules, PD-L1 (B7-H1, CD274), is widely expressed on tumor cells and has been shown to mediate T-cell inhibition. However, attempts to correlate PD-L1 tumor expression with negative prognosis have been conflicting. To better understand when PD-1/PD-L1-mediated inhibition contributes to the functional impairment of tumor-specific CD81 T cells, we varied the levels of antigen density and/or PD-L1 expression at the surface of tumor cells and exposed them to CD8 1 T cells at different levels of functional exhaustion. We found that the gradual reduction of cognate antigen expression by PD-L1-expressing tumor cells increased the susceptibility of partially exhausted T cells to PD-1/PD-L1-mediated inhibition in vitro as well as in vivo.In conclusion, chronically stimulated CD8 1 T cells become sensitive to PD-1/PD-L1-mediated functional inhibition upon low antigen detection; a setting which is likely involved during tumor-immune escape.

PD‐1 expression by canine T cells and functional effects of PD‐1 blockade

“…PD‐L1 expression by tumour cells has been shown to suppress the function of tumour infiltrating T cells . To model this effect in vitro , a canine tumour cell line (MH‐1) with high constitutive expression of PD‐L1 as described recently was used to suppress T‐cell activation.…”

Interferon‐induced programmed death‐ligand 1 (PD‐L1/B7‐H1) expression increases on human acute myeloid leukemia blast cells during treatment

“…In vitro studies indicated that activation or inhibition of T cells in AML depends on the level of PD-L1 expression, which might be modified by chemotherapy (34). In contrast, our group has found in a murine solid tumor model that the antigen density on tumor cells plays a more relevant role than the amount of PD-L1 expression itself for T-cell inhibition (35). What is without doubt though is that PD-L1 expression within the tumor environment can be enhanced by IFN production from infiltrating tumor-specific T cells and thus restrict their own function via PD-1 (28,36), which we also found to be expressed on the majority of T cells from the BM aspirates.…”

“…by reduction of the antigen density and/or additional upregulation of BTLA, LAG, or TIM‐3, will shift tumor immune control towards tumor immune escape. Indeed, recent preclinical experiments and in situ analysis of tumor‐specific T cells support such an idea of concerted immune inhibition .…”

Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation

“…Blank et al (2006) demonstrated that the blockade of B7H1 on human tumors resulted in enhanced cytolytic activity of tumor-infiltrating lymphocytes and cytokine production of T-helper cells when interacting directly with the tumor, explaining the aggressiveness associated with B7H1 expression in DTC even that these tumors are frequently associated with signals of antitumor immune response , 2012a, Cunha & Ward 2012. Recently, Kaiser et al (2012) found that chronically stimulated CD8C lymphocytes become sensitive to B7H1-mediated functional inhibition upon low antigen detection, suggesting that immune escape may be orchestrated by both B7H1 mechanism and tumor antigen density. In fact, Kaiser's results are coherent with our previous data, demonstrating that the pattern of immune cells infiltrating DTC is closely associated with molecular markers of these tumors (Cunha et al 2012a).…”