Du et al. describe a patient with non-small cell lung cancer who rapidly progressed after treatment with radiotherapy and anti-PD-1, and was found to have PD-1 expressed on the tumor. In a murine PD-1-expressing M109 lung cancer cell line, knocking out or blocking PD-1 increased cell viability, while overexpressing PD-1 or treating with soluble PD-L1 reduced viability in vitro; PD-1 blockade accelerated M109 tumor growth in vivo. Tumor-intrinsic PD-1 expression was observed in about 3-10% of lung cancer tissue samples examined.
Anti-PD-1 immunotherapy is the standard of care for treating many patients with nonsmall
cell lung cancer (NSCLC), yet mechanisms of treatment failure are emerging. We present a
case of NSCLC, who rapidly progressed during a trial (NCT02318771) combining palliative
radiotherapy and pembrolizumab. Planned tumor biopsy demonstrated PD-1 expression by
NSCLC cells. We validated this observation by detecting PD-1 transcript in lung cancer cells and
by co-localizing PD-1 and lung cancer-specific markers in resected lung cancer tissues. We
further investigated the biological role of cancer-intrinsic PD-1 in a mouse lung cancer cell line,
M109. Knockout or antibody blockade of PD-1 enhanced M109 viability in-vitro, while PD-1
overexpression and exposure to recombinant PD-L1 diminished viability. PD-1 blockade
accelerated growth of M109-xenograft tumors with increased proliferation and decreased
apoptosis in immune-deficient mice. This represents a first-time report of NSCLC-intrinsic PD-1
expression and a potential mechanism by which PD-1 blockade may promote cancer growth.
