Nav: Home

PD-1/PD-L1 inhibitors treatment in lung cancer: Brightness and challenge

May 18, 2020

Lung Cancer is a leading cause of death worldwide, accounting for an estimated 2.09 million new cases in 2018 according to WHO, which is also the leading cause of cancer-related mortality in China [1].

Immunotherapy has been recognized as one of the most significant breakthroughs in lung cancer therapy during the last decade. Immune-oncology (I-O) can be classified into three categories: (1) active immunity includes vaccines, cytokines, and checkpoint inhibitors; (2) passive immunity includes adoptive cell infusion and targeted monoclonal antibodies; (3) hybrid immunity are combined of active and passive methods. Among them, Immune checkpoints were considered as the most promising targets, whose existence helps to dampen or terminate immune activity to guard against autoimmunity and allow for self-tolerance in normal physiological conditions. However, these immune checkpoint pathways can be tricked and hijacked by tumors to evade the attack of immunity system. Checkpoint inhibitors can reactivate the antitumor immunity, delay tumor growth and lengthen the survival by blocking this pathway.

PD-1 is a member of CD28 family which is expressed in several kinds of immune cells, especially in activated CD8+T cells, CD4+T cells, and B cells in peripheral tissues[2].PD-1 has two binding ligands, PD-L1(B7-H1 or CD274) and PDL2(B7-DC or CD273). PD-L1 is expressed on activated T cells, B cells, macrophages, dendritic cells and cancer cells, and the expression of PD-L2 is limited, mainly in activated macrophages, dendritic cells and a small number of tumor cells. The binding of PD-1/PD-L1 suppresses the proliferation, ¬¬survival of the cytotoxic T lymphocyte, induces the apoptosis process of infiltrative T cells and reduces the production of cytokines [3, 4]. PD-L1 is expressed in 27% to 57% of NSCLC patients [5] .The PD-1/PD-L1 pathway plays a vital role in the immune escape of tumor cells [6, 7]. PD-1 or PD-L1 inhibitors block the inhibitory T-cell signaling, and reactivating the antitumor activity of CD8+ T cells [8]. Tumor cells escape the immune response through the upregulation of PD-L1 to inhibit the action of T cells. Basing on this background, many drugs targeting the PD-1 pathway are under development, and clinical trials of drugs for the PD-1 pathway have been conducted.

However, the proportion of patients who can benefit from ICIs is relatively small. For instance, only 20-25% of NSCLC patients showed a sustainable response to ICIs[9]. Therefore, the discovery and exploration of clinical or biological biomarkers for ICIs is urgent and meaningful. The aim of this approach is to find out the people who may benefit from checkpoint inhibitors and improve the whole cost-effectiveness. However, on account of the complexity of the relationship between tumor and immune-microenvironment, the factors affect the clinical effect of ICIs are multi-dimensional, such as PD1/PD-L1 expression, tumor mutation burden (TMB), Specific Gene Mutations and even Gut Microbiome, et al.

In this brightness and challenges, researchers describe the progress made so far, including the PD-1/PD-L1 inhibitors in clinical practice in lung cancer, followed by their understanding of how biomarkers can be utilized to figure out the most likely beneficiary from ICIs. In conclusion, this article highlights the current clinical trials for the accumulation of knowledge of primary and acquired resistance to improve the clinical outcomes.
This research was funded by the National Key R&D Program of China (2016YFC1303300), the National Natural Science Foundation of China (81672272), Shanghai Municipal Science & Technology Commission Research Project (17431906103), Shanghai Chest Hospital Project of Collaborative Innovation?YJXT20190105?and the Clinical Research Plan of SHDC (16CR3005A).

[1] W. Chen, R. Zheng, H. Zeng, S. Zhang, Epidemiology of lung cancer in China, Thoracic cancer, 6 (2015) 209-215.

[2] Y. Agata, A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, T. Honjo, Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes, Int Immunol, 8 (1996) 765-772.

[3] K. Karwacz, C. Bricogne, D. MacDonald, F. Arce, C.L. Bennett, M. Collins, D. Escors, PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells, EMBO Mol Med, 3 (2011) 581-592.

[4] D.M. Pardoll, The blockade of immune checkpoints in cancer immunotherapy, Nat Rev Cancer, 12 (2012) 252-264.

[5] Y.B. Chen, C.Y. Mu, J.A. Huang, Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study, Tumori, 98 (2012) 751-755.

[6] Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, N. Minato, Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade, Proc Natl Acad Sci U S A, 99 (2002) 12293-12297.

[7] J.M. Taube, R.A. Anders, G.D. Young, H. Xu, R. Sharma, T.L. McMiller, S. Chen, A.P. Klein, D.M. Pardoll, S.L. Topalian, L. Chen, Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape, Sci Transl Med, 4 (2012) 127ra137.

[8] E.B. Garon, N.A. Rizvi, R. Hui, N. Leighl, A.S. Balmanoukian, J.P. Eder, A. Patnaik, C. Aggarwal, M. Gubens, L. Horn, E. Carcereny, M.J. Ahn, E. Felip, J.S. Lee, M.D. Hellmann, O. Hamid, J.W. Goldman, J.C. Soria, M. Dolled-Filhart, R.Z. Rutledge, J. Zhang, J.K. Lunceford, R. Rangwala, G.M. Lubiniecki, C. Roach, K. Emancipator, L. Gandhi, K.-. Investigators, Pembrolizumab for the treatment of non-small-cell lung cancer, N Engl J Med, 372 (2015) 2018-2028.

[9] C. Kaderbhaï, Z. Tharin, F. Ghiringhelli, The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer, Cancers, 11 (2019).

Science China Press

Related Lung Cancer Articles:

'Social smokers' face disproportionate risk of death from lung disease and lung cancer
'Social smokers' are more than twice as likely to die of lung disease and more than eight times as likely to die of lung cancer than non-smokers, according to research presented at the European Respiratory Society International Congress.
Lung cancer therapy may improve outcomes of metastatic brain cancer
A medication commonly used to treat non-small cell lung cancer that has spread, or metastasized, may have benefits for patients with metastatic brain cancers, suggests a new review and analysis led by researchers at St.
Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Lung transplant patients face elevated lung cancer risk
In an American Journal of Transplantation study, lung cancer risk was increased after lung transplantation, especially in the native (non-transplanted) lung of single lung transplant recipients.
Proposed cancer treatment may boost lung cancer stem cells, study warns
Epigenetic therapies -- targeting enzymes that alter what genes are turned on or off in a cell -- are of growing interest in the cancer field as a way of making a cancer less aggressive or less malignant.
Are you at risk for lung cancer?
This question isn't only for people who've smoked a lot.
Better equipped in the fight against lung cancer
Lung cancer is the third most common type of cancer in Germany and the disease affects both men and women.
New liquid biopsy-based cancer model reveals data on deadly lung cancer
Small cell lung cancer (SCLC) accounts for 14 percent of all lung cancers and is often rapidly resistant to chemotherapy resulting in poor clinical outcomes.
Cancer drug leads to 'drastic decrease' in HIV infection in lung cancer patient
Doctors in France have found the first evidence that a cancer drug may be able to eradicate HIV-infected cells in humans.
More Lung Cancer News and Lung Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at     You can read The Transition Integrity Project's report here.