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Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1)axis is well known as the system resulting in the inhibition of immune responses and promotion of self-tolerance. The clinical indications for immune checkpoint inhibitors( ICIs), including the targeting of PD-1/PD-L1 axis, are dramatically expanding. However, since ICIs have been found to be ineffective or resistant in some types of cancer, the development of more effective combination therapies or predictors and biomarkers of efficacy are expected. On the other hand, we have been focusing on the tumor microenvironment(TME)as a therapeutic target, and have been analyzing the function of cancer-associated fibroblasts(CAFs), which play a central role in TME. Recently, CAFs are known to induce tumors to an immunosuppressive state, suggesting that ICIs may not be effective in such a cancer microenvironment. In this review, we demonstrated the impact of PD-L1 positivity in cancer cells and CAFs by immunohistochemistry for resected specimens. In addition, we evaluated the potential of PD-L1-positve CAFs for therapeutic target and biomarker for ICIs.

The purpose of this study was to evaluate the prognostic significance of programmed cell death-ligand 1(PD-L1)expression and CD8+T cells in the immune microenvironment. From January 2011 to December 2011, we retrospectively examined 31patients with Stage III colorectal cancer. PD-L1expression and CD8+T cell counts were evaluated by immunohistochemical study using whole-tumor slides. PD-L1expression in cancer cells(PDCC)and in tumor-infiltrating stromal cells(PDSC)was divided into high(H)and low(L)groups. CD8+T cells were counted in the core of the tumor(CDCT)and in the invasive margin of the tumor area(CDIM), and divided into high(H)and low(L)groups. Based on a median follow-up time of 69.3 months, the 5-year overall survival and disease-free survival of all patients were 74.2% and 64.5%, respectively. The overall survival was significantly longer for patients in the CDIM-H group(82.6%)than those in the CDIM-L group(50.0%; p= 0.034). Patients in the PDSC-H group also tended to have superior overall survival than those in the PDSC-L group(84.2% and 58.3%, respectively, p=0.094). In conclusion, both CD8+T cells and tumor-infiltrating immune cells with PD-L1may indicate antitumoral function in patients with Stage III colorectal cancer.

There are many reports on the association between infiltrating immune cells andcancer prognosis. It is generally thought that cancer cells escape from the immune surveillance system in vivo. Cells associatedwith tumor immunosuppressive mechanisms include macrophages, regulatory T cells, bone marrow-derived immunosuppressive cells(MDSC), andneutrophils. These immunosuppressive cells enhance the production of TGF-b andIL -10 andthe expression of PDL-1 by cytokines producedby stromal cells such as cancer cells andfibroblasts, thereby inducing cytotoxic T cells lymphocytes(CTL). On the other hand, it has been proved that CD8+ T cells react in an antigen-specific manner even in advanced gastric cancer, suggesting the possibility that memory T cells, NK cells andNKT cells in gastric cancer tissues correlate with goodprognosis. Recently, it has been reportedthat the presence of follicular lymphoidstructure calledtertiary lymphoidstructure(TLS)in gastric cancer tissue is associatedwith favorable prognosis. Although immune responses are suppressedin gastric cancer tissues, the effectiveness of an immune checkpoint inhibitor(anti-PD-1 antibody)has been provedin 2017. The tumor-infiltrating immune cells is known as a predictive effect biomarker. As cancer genome research progresses, which type of immune response is induced is gradually being elucidated in near future. Thus, assessing the invasive morphology and function of various tumorinfiltrating immune cells is considered to be extremely important in Precision Medicine for gastric cancer.

Immune checkpoint blockade therapy using anti-PD-1 or anti-PD-L1 antibodies can unleash anti-tumor immunity and induce durable remission in a variety ofhuman cancers. However, the regulatory mechanisms of PD-L1 expression mediating immune evasion ofcancer cells have not been fully elucidated, including the genetic alterations causing PD-L1 overexpression. Recently, we have reported a novel genetic mechanism ofimmune evasion associated with structural variations(SVs)disrupting the 3'-untranslated region(UTR)ofthe PD-L1 gene in various malignancies, such as aggressive lymphomas and gastrointestinal cancers. Despite a heterogenous nature ofthese SVs, they are closely associated with a marked upregulation of PD-L1 expression, which augments tumor growth and escape from anti-tumor immunity. Here we present an overview of the regulatory mechanisms of PD-L1 expression in cancer cells, highlighting the genetic mechanisms of PD-L1 constitutive activation, with specific focus on PD-L1 3'-UTR disruption.

The response rate of anti-PD-1/anti-PD-L1antibody alone is about 20 to 30%and the development of biomarker for them is important to know their indication. Based on previous reports and our research results, we suggested that basic candidates of biomarker for anti-PD-1/anti-PD-L1antibody are the expression of PD-L1and HLA class I on cancer cells and the invasion of CD8 positive T cells in tumor microenvironment. Furthermore, in addition to these conditions, regulatory T cells and immune cells expressing PD-L1in tumor microenvironment, and microsatellite instability of cancer cells will be considered in the future.

Recently developed immune checkpoint inhibitors, such as anti-PD-1 antibodies, have shown a clear improvement in clinical efficacy compared with conventional cytotoxic chemotherapy in the treatment of patients with advanced melanoma. Treatment with anti-PD-1 antibodies has resulted in improved objective response rates, longer durations of response, and longer overall survival rates. Although the incidence rate of adverse events associated with anti-PD-1 antibodies is lower than that associated with cytotoxic agents, characteristic severe adverse events such as pneumonia, endocrinopathy, and colitis can occur. A recent clinical trial that evaluated the utility of an anti-PD-1 antibody in combination with an anti-CTLA-4 antibody reported that the treatment enhanced clinical efficacy in terms of response rate and progression-free survival. However, the incidence of adverse events and treatment discontinuation also increased. For optimal selection of immune checkpoint inhibitors for treating patients with advanced melanoma, biomarkers capable of predicting clinical efficacy, prognosis, and adverse events in each patient need to be identified. In addition, novel combination therapies, including immune checkpoint inhibitors and MAP kinase pathway-targeting agents, should result in more favorable clinical responses and prolonged overall survival rates.

HLA class I and PD-L1expressed on cancer cells play a pivotal role in the CTL recognition mechanism against cancer cells in the tumor microenvironment. It is well known that IFN-g upregulates PD-L1as well as HLA class I expression in cancer cells, and it is suggested that TILs, including CTL, produce IFN-g in the tumor microenvironment. Therefore, there is a possibility that IFN-g produced by activated TILs upregulate both HLA class I and PD-L1expression in cancer cells in the tumor microenvironment. We propose that the anti-tumor effect of CTL could be enhanced if the inhibition of CTL recognition mechanism against cancer cells via the PD-1/PD-L1pathway is canceled by anti-PD-1or anti-PD-L1antibody.

Melanoma is a highly immune tumor, and tumor-specific T lymphocytes are occasionally induced. Recent progress in tumor immunology has made it possible to clinically develop new medicines targeting immune checkpoint molecules, such as cytotoxic T lymphocyte antigen 4(CTLA-4), programmed cell death 1(PD-1), and programmed cell death 1 ligand 1(PD-L1). CTLA-4 is expressed on naïve T cells and regulatory T cells. Ipilimumab, an anti-CTLA-4 antibody, shows a distinct durable clinical benefit by inhibiting the immunosuppressive function of CTLA-4. PD-1, which is expressed on activated T cells, inhibits T cell responses against tumor cells. The antibodies against PD-1, nivolumab and pembrolizumab, produce anti-tumor responses in melanoma and other cancers due to T cell reactivation. Furthermore, clinical trials of combination therapies using immune checkpoint blockades with molecularly targeted therapies and other chemotherapeutic agents are being conducted. However, immune checkpoint blockades frequently cause immune-related adverse events. Targeted therapies to immune checkpoint molecules are expected to be promising strategies for treatment of melanoma and other cancers.

Immune checkpoint blockade therapy has recently attracted great attention in the area of oncology. In Japan, since 2014, an anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab have been available for the treatment of patients with malignant melanoma, and nivolumab has been available for patients with non-small cell lung cancer. Clinical trials using these drugs and other immune checkpoint inhibitors are currently in progress worldwide. The immune checkpoint blockade therapy is a promising new cancer therapy; however, not all patients with cancer can benefit from this therapy. Recent evidence shows that markers reflecting the extent of genetic mutation accumulation, including mutation burden, non-synonymous mutation that produces neoantigen, and microsatellite instability, possibly serve as promising marker to predict who can benefit from the immune checkpoint blockade therapy. Here, I introduce the recent evidence and discuss the correlation between genetic mutation accumulation and clinical outcome of immune checkpoint blockade therapy.

The dramatic and long durable anti-tumor effect of immune checkpoint blockade, such as anti-CTLA-4 Ab, anti-PD-1 Ab, and anti-PD-L1 Ab was surprised the world. In addition, CAR-T cell therapy that target the CD19 indicates a very high response rate to the CD19-positive hematologic malignancies. Now, no one doubts the presence of immunity against cancer.  Further, accordingly, tumor-specific neoantigen are attention now, the clinical trials of individualized peptide vaccination that target patient individual neoantigens has begun in the Western. On the other hand, the peptide vaccine therapy that target common self-antigen is not yet been approved in Japan, the development is struggling.  In this paper, I overview the cancer immunotherapy and neoantigen and introduce some development of cancer immunotherapy in Japan.

Recent studies have revealed that tumor cells can acquire several mechanisms to evade host immunity in the tumor microenvironment, called cancer immune escape. One of the most important mechanisms in this system is an immunosuppressive co- signal, called immune checkpoint, in the programmed cell death-1(PD-1)/programmed death-ligand 1(PD-L1)pathway. PD-1 is mainly expressed on activated T cells, while PD-L1 is frequently expressed on tumor cells. Inhibition of the interaction between PD-1 and PD-L1 enhances T-cell response and mediates antitumor activity. Several clinical trials by several institutions and pharmaceutical companies in the world have shown the antitumor efficacy of PD-1/PD-L1 signal blockade in patients with some solid and hematological malignancies. Production of some drugs for use in anti-PD-1 therapies are on the verge of completion. Herein, we provide a background about the PD-1/PD-L1 signal and describe some previously performed foreign clinical trials, including a trial in our department.