Cancer immunotherapies targeting the PD-1 signaling pathway
Iwai et al. Journal of Biomedical Science
Cancer immunotherapies targeting the PD-1 signaling pathway
Yoshiko Iwai 0 3
Junzo Hamanishi 0 2
Kenji Chamoto 0 1
Tasuku Honjo 1
0 Equal contributors
1 Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University , Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501 , Japan
2 Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University , 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 , Japan
3 Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health Japan , Kitakyushu-shi, Fukuoka 807-8555 , Japan
Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. However, the failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research on combination therapies and predictive biomarkers. Here we summarize the development of PD-1blockade immunotherapy and current issues in its clinical use.
PD-1; PD-L1; Cancer immunotherapy; Immune checkpoint
Background
Cancer immunotherapy, although controversial for many
years, reached a turning point in 2014. Antibodies that
specifically block PD-1 were approved for melanoma in
2014 and for non-small-cell lung cancer (NSCLC) in
2015 in the United States, European Union, and Japan.
The success of clinical trials with novel drugs targeting
immune-checkpoint molecules such as PD-1 led to a
paradigm shift in cancer treatment. Since a PD-1
blockade targets lymphocytes rather than cancer cells, it has a
long-term therapeutic effect that persists even when
cancers cause mutations. Furthermore, the PD-1
blockade is effective against many types of tumors because it
enhances the anti-tumor activity of cytotoxic T
lymphocytes (CTLs), which recognize various tumor-specific
antigens. Several companies are currently conducting
phase 3 trials for different tumor types, including
renalcell cancer (RCC), bladder cancer, head and neck cancer,
ovarian cancer, and brain cancer. Although PD-1
blockade has dramatically improved the response rate for
several cancers, three questions remain to be answered: 1)
Why do some patients not respond to PD-1 blockade?
2) What is the best combination therapy using PD-1
blockade? 3) What predictive biomarkers can be used to
distinguish responsive and unresponsive patients? Here
we review the development of immunotherapy targeting
the PD-1/PD-L1 signaling pathway and discuss the
issues that still need to be resolved in clinical studies.
History of cancer immunotherapy
The concept of cancer immunotherapy goes back to the
late nineteenth century. In 1891, a young New York
surgeon named William Coley began intra-tumoral
injections of bacterial products and observed tumor
shrinkage in patients with sarcoma [
1
]. Almost a century
later, the role of dendritic cells and their receptors in
sensing microorganisms in the innate immune system
was discovered [
2, 3
]. The molecular identification of
cancer antigens created new approaches for effective
immunotherapies [4]. In addition, the importance of IFN-γ
and adaptive immunity in cancer immunosurveillance
was demonstrated in preclinical tumor models using
IFN-γR−/− and RAG2−/− mice [
5
]. These findings
stimulated research into strategies to induce anti-tumor
responses and led to immunotherapies such as cytokine
therapy, peptide vaccine, dendritic-cell vaccine, and
adoptive T-cell therapy. Most of these therapies were
unsuccessful, and one primary reason was a lack of
understanding of the existence and importance of immune
checkpoints [
6
].
Immune checkpoints
T-cell activating (accelerator) and inhibitory (brake)
receptors regulate the balance between immune response
and immune tolerance. The activation of naïve T cells
requires both antigen presentation (signal 1) and a
second signal sent through costimulatory receptors such as
CD28 (signal 2) (Fig. 1) [
7
]. When ligated by B7
molecules such as CD80 (B7-1) or CD86 (B7-2), CD28
coreceptors on T cells deliver a positive costimulatory signal,
whereas CTLA-4 coreceptors deliver a negative
coinhibitory signal. PD-1, like CTLA-4, belongs to the
CD28 family and delivers a negative signal when it
interacts with its ligands, PD-L1 (B7-H1 or CD274) and
PDL2 (B7-DC or CD273), which belong to the B7 family
(Fig. 1) [
8–10
].
T cells have immune checkpoints such as PD-1 and
CTLA-4 to reduce autoimmune responses against
selftissues by overly exuberant immune responses to
infection. While most cancer immunotherapies accelerate
Tcell activity, immune-checkpoint inhibitors release the
immune system’s brakes (...truncated)