Introdução e Metodologia

Tumor infiltrate PD-L1 expression as a predictive biomarker in Non-Small-Cell Lung Cancer

Maria Clara Lemos-Santos, Marina Yuri Kadekaru, Rachel Kalkaslief

1.Introduction

 NSCLC accounts for approximately 85% of the cases of lung cancer (1, 2), which was considered one of the main causes of worldwide cancer death among males and females in 2012 (3). Despite the wide range of conventional therapies available for metastatic NSCLC (2), the prognosis still remains unfavorable in cases of advanced disease (1) and chemotherapy apparently no longer has a dramatic efficiency in terms of survival in patients (4), reinforcing the need for alternative paths in NSCLC treatment.

 Anti-tumor intervention based on immune system responses is not exactly new, with studies dating back to mid 1970s (5). However, researches about immunotherapeutic agents have been facing great evolution in recent years, especially the ones referring to therapeutic vaccine development and to immune checkpoint inhibition (6, 7). These strategies could play a major role in cancer therapy as an alternative treatment for the standard therapies, due to their significant treatment responses in patients as well as manageable toxicities. (7) The combination of immunotherapy with traditional therapy or other immunotherapeutic agent is another topic commonly discussed (8), since objective response rates were seen in some cases of combined therapy, such as the treatment with anti-PD-1 and anti-CTLA4 in melanoma (9, 10).

 Inside the tumor microenvironment, as tumor cells accumulate several mutations throughout countless cell cycles a set of tumor antigens is also produced, which could be easily recognized by the immune system as a non-self substance, resulting in activation of T-cell’s response through co-stimulatory signals. However, in some cases the inhibitory signals overbalance the co-stimulatory ones, leading to a non-immunogenic tumor. Immune checkpoints consist of various signaling pathways which are responsible for the immunomodulation effects. Under physiological conditions, they are essential for providing self-tolerance and avoiding tissue damage, while in tumors they contribute to immune resistance (11). PD-L1 expression in tumors and in tumor infiltrate is one of the main mechanisms responsible of inducing immune escape. To determine predictive biomarkers related to tumor response and clinical efficacy of these drugs is very useful to select those best candidates to immunotherapy.

 The next generation of immunotherapy consists of immune checkpoint inhibitors, e.g., monoclonal antibodies that block the interaction of PD-1 on lymphocytes and PD-L1 on antigen presenting cells (APCs) and tumor cells, and are applicable to melanoma, Hodgkin lymphoma, bladder cancer and non-small cell lung cancer (NSCLC), among others. (8) There is a considerable amount of on-going clinical trials targeting PD-L1, most of them happening in the United States and Europe. (12) Nivolumab (BMS-936558), for example, was proved in a Phase 3, randomized, double-blind study to be more beneficial than Dacarbazine, with significant improvement of overall survival in patients with previously untreated, unresectable, or metastatic melanoma. (13, 14) Nivolumab is also being compared to Docetaxel in a Phase 3 study for previously treated metastatic non-squamous NSCLC, demonstrating significant improvement in overall survival, response rate, and progression-free survival, regardless of PD-L1 expression level. (15, 16)  

 Because of that, there are some recruiting trials for NSCLS involving several drugs, for example Gefitinib in combination with MEDI4736 (anti PD-L1) (17), Atezolizumab (18), Pembrolizumab (MK-3475/SCH 900475) (19), Avelumab (20), MEDI4736 + Tremelimumab combination therapy (21) and others, which shows how current and important immunotherapy and the PD-L1/PD-1 axis blockage are, especially concerning this particular tumor.  

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Map showing number of on-going studies with NSCLC and PD-L1 (8)

 Nonetheless, not all patients with NSCLC had significant benefits from immune checkpoint blocking drugs. With this in mind, researches aiming to identify and select patients who would respond to these therapies are of utmost importance. The expression of PD-L1 in tumor microenvironment has been considered a potential predictive biomarker for many authors, especially the PD-L1 expression in tumor cells (22, 23, 24). But there are few studies acknowledging the predictive potential of PD-L1 expression in tumor-infiltrating immune cells which suggested that higher immune cells expression of this molecule in tumor microenvironment could be possibly related to better clinical responses (25, 26, 27).

This review will discuss specifically the tumor infiltrate expression of PD-L1, an immune checkpoint molecule, in NSCLC and its potential as a predictive biomarker for PD-1/PD-L1 blocking immunotherapy.

2. Methods

2.1 Terms for search

4 Medical databases were selected for research: Pubmed, Scopus, Lilacs and Web of Science. Terms for search were used as free search and as controlled vocabulary thesaurus when possible (i.e. Pubmed).The terms used were:

-PDL1 and TUMOR INFILTRATING and BIOMARKER

-PDL1 and TUMOR MICROENVIRONMENT and BIOMARKER

-PDL1 and TUMOR INFILTRATING and IMMUNOTHERAPY

-PDL1 and TUMOR INFILTRATING and IMMUNOTHERAPY

-PDL1 and MYELOID CELLS

-PDL1 and DENDRITIC CELLS

-PDL1 and MACROPHAGES

-PDL1 and LYMPHOCYTES and NON SMALL CELL LUNG CANCER

-ANTIGENS, CD274 [MESH]) AND  MYELOID CELLS [MESH]

-ANTIGENS, CD274 [MESH]) AND DENDRITIC CELLS [MESH].

-ANTIGENS, CD274"[MESH]) AND CARCINOMA, NON-SMALL-CELL LUNG [MESH]) AND TUMOR MICROENVIRONMENT [MESH]

-TUMOR MICROENVIRONMENT [MESH]) AND ANTIGENS, CD274 [MESH]

-LYMPHOCYTES, TUMOR-INFILTRATING[MESH]) AND ANTIGENS, CD274 [MESH]) AND CARCINOMA, NON-SMALL-CELL LUNG[MESH]

2.2 Exclusion Criteria

 The criteria for exclusion were:

-Language of the article: Only articles written in Portuguese or English were selected

-Availability of access: articles should have free access or be available due University subscriptions

- Articles with titles or abstracts reporting PD-L1 in infection, autoimmunity or other types of cancer were also excluded

2.3 Inclusion Criteria

The criteria for inclusion were:

-Articles with adequate content, i.e, the expression and role of the molecule PD-L1 in the microenvironment (stroma and cells of the immune system) in context of non-small-cell lung cancer.