Blockade of Tumor-Expressed PD-1 promotes lung cancer growth

Abstract

Anti-PD-1 immunotherapy is the standard of care for treating many patients with non-small 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.

PD-L1 associated with the expression of cancer cell-intrinsic PD-1 and p-S6 proteins and predicted a good prognosis in nasopharyngeal carcinoma

“…In pancreatic cancer, cell-intrinsic PD-1 promoted tumor growth through the Hippo signaling pathway outside the immune system [42]. However, Du et al found that cell-intrinsic PD-1 was presented in NSCLC as a tumor suppressor [43]. In our study, we found that patients with positive PD-1 expression in NPC tissues had shorter survival time, which is consistent with ndings in most malignancies.…”

Differential expression of programmed death‐1 according to the histological differentiation of cutaneous squamous cell carcinoma

“…Yet, little is known about intrinsic PD‐1 pathway effects on tumour cells. Unlike its oncogenic functions in melanoma, blockade of PD‐1 promoted tumour cell proliferation in nonsmall cell lung cancer . Studies on the expression of PD‐L1 in cutaneous squamous cell carcinoma (cSCC) have increased .…”

Hyperprogression Under Immune Checkpoint-Based Immunotherapy—Current Understanding, The Role of PD-1/PD-L1 Tumour-Intrinsic Signalling, Future Directions and a Potential Large Animal Model

“…Multiple recent publications reported that cancer cells express not only PD-L1 but also PD-1 in tumour types such as melanoma, hepatocellular carcinoma, ovarian cancer, and NSCLC [69][70][71]. Until now, it had been believed that the PD-1 receptor could be expressed solely on haematopoietic cells [72].…”

“…Until now, it had been believed that the PD-1 receptor could be expressed solely on haematopoietic cells [72]. Strikingly, in their case report Du et al described rapid NSCLC progression (hyperprogression) in a patient treated with pembrolizumab [71]. Analysis of the tumour biopsy found NSCLC cells expressing the PD-1 receptor.…”

“…A further study observed proliferation of tumour cells in the murine model after anti-PD-1 treatment. The molecular mechanism behind this phenomenon remains unknown, but authors detected an increase in cells expressing proliferation marker Ki67 and a decrease in apoptosis marker Caspase-3 [71]. In certain cancers, acute T-cell lymphocytic leukaemia as a prime example, PD-1 is proposed to function as a tumour suppressor [55].…”