Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC

Treatment with anti-PD-1 and anti-PD-L1 therapies has shown durable clinical benefit in non-small cell lung cancer (NSCLC). However, patients with NSCLC with epidermal growth factor receptor (EGFR) mutations do not respond as well to treatment as patients without an EGFR mutation. We show that EGFR-mutated NSCLC expressed higher levels of CD73 compared with EGFR WT tumors and that CD73 expression was regulated by EGFR signaling. EGFR-mutated cell lines were significantly more resistant to T cell killing compared with WT cell lines through suppression of T cell proliferation and function. In a xenograft mouse model of EGFR-mutated NSCLC, neither anti-PD-L1 nor anti-CD73 antibody alone inhibited tumor growth compared with the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth, increased the number of tumor-infiltrating CD8(+) T cells, and enhanced IFN-gamma and TNF-alpha production of these T cells. Consistently, there were increases in gene expression that corresponded to inflammation and T cell function in tumors treated with the combination of anti-PD-L1 and anti-CD73. Together, these results further support the combination of anti-CD73 and anti-PD-L1 therapies in treating EGFR-mutated NSCLC, while suggesting that increased T cell activity may play a role in response to therapy.

Automated summary

Anti-PD-1 and anti-PD-L1 therapies are effective in non-small cell lung cancer (NSCLC), but less so in patients with EGFR mutations. This study found that EGFR-mutated NSCLC expressed higher levels of CD73 and were more resistant to T cell killing. Combining anti-PD-L1 and anti-CD73 therapies significantly inhibited tumor growth and increased T cell activity in EGFR-mutated NSCLC. These findings support the use of combination therapy in this patient population.