PD-L1 Expression and Tumor Infiltrating Lymphocytes in Neurofibromatosis Type 1-Related Benign Tumors and Malignant Peripheral Nerve Sheath Tumors:An Implication for Immune Checkpoint Inhibition Therapy

Background Neurofibromatosis type 1(NF1)is an autosomal dominant inherited disorder.It can affect multiple systems of the body and cause severe disfigurement and discomfort in these patients.There are two types of neurofibromas,named cutaneous and plexiform neurofibromas.The latter type may transform into malignant peripheral nerve sheath tumors(MPNSTs).Surgical resection is difficult to perform owing to the complex tissue structure of neurofibromas;therefore,it is necessary to develop novel and effec­tive therapies for the treatment of these tumors.Programmed cell death protein 1(PD-1)/programmed cell death-ligand 1(PD-L1)-related immune checkpoint inhibitors have been proven effective for various cancers,and the positive expression of PD-L1 and tumor-infil­trating lymphocytes(TILs)has been recognized as a biomarker for the response to immune checkpoint therapy.Methods We conducted immunohistochemistry(IHC)staining to detect PD-L1 expres­sion in plexiform neurofibroma and MPNST tissue samples.Reverse transcription-poly­merase chain reaction(RT-PCR)and western blotting were performed to detect PD-L1 and PD-1 expression in MPNST cell lines.IHC staining was used to show immune cell infiltra­tion in NF1 and MPNST tissues.Results IHC staining showed PD-L1 positive expression in neurofibromas and MPNST tumor tissues.In addition,qPCR and western blotting showed high expression of PD-L1 in MPNST tumor cells.IHC staining revealed that aberrant T lymphocytes infiltrated the plexiform neurofibroma and MPNST tumor tissues.Conclusion These results indicate that immune checkpoint mechanisms may play a pivotal role in the development of NF1-related tumors,and immune checkpoint inhibitors may be effective for managing neurofibromas and MPNSTs.Combined therapy with other molecular agents may be explored in the future.

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

Immune-related endocrine disorders in novel immune checkpoint inhibition therapy

Immune checkpoint inhibition against advance malignancies was named breakthrough discovery by the science magazine in 2013.In numerous clinical studies,monoclonal antibodies against the immune checkpoints,CTLA4,PD1 and PD1 ligand PDL1 have shown promising tumor response in different type of metastatic malignancies.The adverse events are autoimmune-related.The endocrine disorders,hypophysitis and thyroiditis are among the most common side effects associated with immune checkpoint inhibition treatment.Hypophysitis,a very rare endocrine disorder occurs in about one tenth of the patients receiving anti-CTLA4 treatment.Thyroiditis,on the other hand,is more commonly seen in patients receiving anti-PD1 treatment.In addition,both thyroiditis and hypophysitis are common in patients receiving combination treatment with anti-CTLA4 and anti-PD1 treatment.The time to onset of hypophysitis and thyroiditis is short.Most of the endocrine disorders occur within 12 weeks after initiation of the immune checkpoint inhibition therapy.Hypophysitis can manifest as total anterior pituitary hormone deficiency or isolated pituitary hormone deficiency.Diabetes insipidus is rare.TSH and gonadotropin deficiencies may be reversible but ACTH deficiency appears permanent.Thyroiditis can present as hypothyroidism or thyrotoxicosis followed by hypothyroidism.Hypothyroidism appears irreversible.Early identifying the onset of hypophysitis and thyroiditis and proper management of these endocrine disorders will improve the quality of the life and the outcome of this novel immunotherapy.

The role of immune checkpoint inhibitors in triple-negative breast cancer: recent developments and future perspectives

Triple-negative breast cancer(TNBC)represents the subtype of breast cancer with the most aggressive biological behavior and the worst prognosis compared to other breast cancers.Metastatic TNBC is characterized by a high proliferative index,rapid progression with metastases to the viscera and central nervous system,and generally an unfavorable prognosis with a survival of about one year.It is,therefore,necessary to identify specific targets and more effective treatments for patients with TNBC.Evidence of the effect of the tumor immune microenvironment on clinical outcomes is considered a significant issue in breast cancer therapeutics.Compared to other subtypes of breast cancer,TNBC is characterized by a higher mutational burden and is recognized as the most immunogenic among them.Based on these findings,immune checkpoint inhibition was evaluated in TNBC with encouraging results.Indeed,enhancing antitumor immunity in TNBC by blocking the cytotoxic T-lymphocyte-associated antigen 4(CTLA-4)axis or the programmed cell death-1(PD-1)receptor/programmed death-ligand 1(PD-L1)pathway is a promising treatment option.In this review,we examine the role of monoclonal antibodies targeting CTLA-4 and PD-1/PD-L1 in this breast cancer subtype and discuss combination approaches for early and advanced disease.

Nanomedicine integrating the lipidic derivative of 5-fluorouracil,miriplatin and PD-L1 si RNA for enhancing tumor therapy

Immunosuppressive microenvironments present critical problems in clinical chemotherapy.To regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied clinically.In this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for chemo-immunotherapy.In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages.Furthermore,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition.The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

The promise of immunotherapy in genitourinary malignancies

A broad understanding of the tumor immune landscape has led to a revolution of immune checkpoint inhibitors in the treatment of multiple cancer types.In genitourinary malignancies,immune checkpoint inhibitors have improved outcomes for patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma;however,these treatments have not yet proven broadly beneficial for patients with metastatic prostate cancer.Numerous prospective trials are ongoing to further improve outcomes with immunotherapy combinations and for biomarker development to predict benefit from immune checkpoint inhibition.This perspective article highlights our current immunotherapy approaches in each of the genitourinary malignancies and the ongoing clinical trials that may inform our future treatments in renal,urothelial,and prostate cancers.