Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

Abstract

Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1 þ TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P ¼ 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro-and liposarcomas), but showed the inverse association with the number of detected mutations (P ¼ 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P ¼ 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P ¼ 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities. Cancer Epidemiol Biomarkers Prev; 23(12); 2965-70. Ó2014 AACR.

PD-L1 Expression in Tumor Metastasis is Different Between Uveal Melanoma and Cutaneous Melanoma

“…PD-L1 expression has been well established in MCM using several different assays [27,29]. Regarding PD-L1 expression in MUM, only limited data from in vitro cell line analysis are available [31].…”

“…Expression of intratumoral PD-1 on TILs was determined using an anti-PD-1 monoclonal antibody (NAT105, Cell Marque, CA, USA), with density assessed as previously described [27]. Tissue slides were reviewed at low power (2-4×) for identification of an area with the highest number of PD-1 + cells.…”

“…Tissue slides were reviewed at low power (2-4×) for identification of an area with the highest number of PD-1 + cells. This 'hot spot' area was then examined under a high power field (40×) to identify and count the number of PD-1 + TILs [27]. PD-1 positivity was determined by counting one or more PD-1 + TILs in a high power field.…”

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

“…Disturbance of this balance in cancers favors tumor progression. Activation of PD1, expressed at the surface of immune cells such as T cells, by its ligand PDL1/CD274, expressed by antigen-presenting cells such as macrophages or B cells, but also by cancer cells, 29 inhibits lymphocyte activation, 30 and promotes T-reg cell development and function, allowing tolerance acquisition or to terminate the immune response. Recently, PD1 and PDL1 inhibitors showed promising antitumor activity with durable response, notably in melanoma and lung, renal and bladder carcinomas, 31,32 where a relationship between PDL1 expression on cancer cells and/or TILs and objective response has been evidenced.…”

PDL1 expression is an independent prognostic factor in localized GIST

“…Cancer cells from different locations have acquired the capacity to express PDL1. 25 The PD1-PDL1 pathway has, thus, been involved in cancer progression. 26,27 Anti-PD1 and anti-PDL1 drugs 28 are being tested in phase 3 clinical trials after very promising results in phase 2 trials.…”