Breast cancer immunology and immunotherapy:targeting the programmed cell death protein-1/programmed cell death protein ligand-1

Historically,breast cancer has been regarded as an immunogenic"cold"tumor.However,the discovery of immune checkpoint inhibitors has made immunotherapy becoming an emerging new treatment modality for breast cancer.This review discusses the immune system,immune features of breast cancer,and the programmed cell death protein-1/programmed cell death protein ligand-1(PD-1/PD-L1)inhibitors used in the treatment of breast cancer.High T lymphocyte infiltration and mutation burden were observed in triple-negative breast cancer and human epidermal growth factor receptor 2 positive breast cancer.Increasing breast cancer immunogenicity and modulating the tumor microenvironment has been reported to improve the therapeutic efficacy of immunotherapy.Recent clinical trials involving PD-1/PD-L1 inhibitors monotherapy in breast cancer has revealed little efficacy,which highlights the need to develop combinations of PD-1/PD-L1 inhibitors with chemotherapy,molecularly targeted therapies,and other immunotherapies to maximize the clinical efficacy.Collectively,the immunotherapy might be a promising therapeutic strategy for breast cancer and several clinical trials are still on-going.

Prognostic significance of PD-L1 expression in patients with colorectal cancer: a meta-analysis

Background The association between the expression of programmed cell death 1(PD-1) or its ligand [programmed cell death ligand-1(PD-L1)] and colorectal cancer(CRC) survival rates remains unclear. Thus, we conducted a meta-analysis to investigate the prognostic value of PD-L1 expression in CRC patients.Methods All eligible studies related to evaluation of PD-L1 expression and survival of CRC patients were searched in PubMed, Medline, Cochrane library, and the EMBASE database. Hazard ratios(HRs) and 95% confidence intervals(CI) of overall survival(OS) were examined to assess the effect of PD-L1 expression on the survival of CRC patients. The outcomes of this meta-analysis were synthesized based on randomeffects model. Subgroup analyses were also performed. Results Seven studies, wherein OS data were stratified according to the expression status of PD-L1, were analyzed. CRC patients showing positive PD-L1 expression were associated with significantly poorer prognoses in terms of overall survival, compared with those displaying negative PD-L1 expression(HR = 1.43, 95% CI: 1.07–1.92; P = 0.02). In the subgroup analyses, H-scores as well as the percentage of stained cells indicated that PD-L1 expression was significantly associated with poor prognosis(HR = 1.90, 95% CI: 1.38–2.62, P < 0.01; HR = 1.81, 95% CI: 1.08–3.03, P = 0.02). Immunohistochemical staining, utilizing a rabbit anti-PD-L1 antibody, revealed significantly superior survival in the PD-L1 negative group compared with the PD-L1 positive expression group(HR = 1.92; 95% CI, 1.40-2.63; P < 0.01). Moreover, PD-L1 expression was significantly associated with poor prognosis when polyclonal antibodies were used(HR = 1.84; 95% CI, 1.30–2.61; P < 0.01). Conclusion Our meta-analysis indicated that PD-L1 expression status is a significant prognostic factor for CRC patients. Positive PD-L1 expression was associated with worse CRC survival. Evaluation via different immunohistochemistry based techniques may partly account for the contradictory results. Therefore, further investigative studies using larger sample sizes are felt to be needed to elucidate the prognostic value of PD-L1 expression in CRC patients.

Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer

Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.

Liposome-coated CaO_(2)nanoblockers for enhanced checkpoint blockade therapy by inhibiting PD-L1 de novo biosynthesis

The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.

Inflammatory pathways in pathological neovascularization in retina and choroid: a narrative review on the inflammatory drug target molecules in retinal and choroidal neovascularization

Objective:We review inflammatory drug targets in retinal and choroidal neovascularization(NV)in narrative manner.Background:Vascular remodeling and angiogenesis are processes typically associated with wound-healing mechanisms intended to minimize ischemia and maintain tissue homeostasis.In the eye,however,these actions primarily deteriorate tissue homeostatic recovery,and could even contribute to the progress of severe conditions,e.g.,blindness.Angiogenesis in diabetic retinopathy(DR)and age-related macular degeneration(AMD)is the primary cause of vision loss in working-age and elderly populations.Current treatment of anti-vascular endothelial growth factor(VEGF)agents has limited action efficacy,working in less than 50%patients.Understanding cellular and molecular networks associated in retinal vascular remodeling may provide an insight to develop novel therapeutic strategies.Methods:Here,we highlight ocular cells-endothelial,mural,retinal pigment epithelium(RPE),glial and macrophages,as well as inflammatory molecules-such as the complement system,stromal derived factor-1,chemokine CXC receptor-4,inflammasome,interleukin-18,programed cell death ligand-1,insulin-like growth factor(IGF)and sphigosin-1-phosphate receptor,associated with retinal and choroidal NV,and discuss their recent and future therapeutic approaches.Conclusions:A deeper understanding on pathogenesis,pathobiology including ocular immunobiology of retinal and choroidal NV will pave the way to expand and overleap the current therapeutic approach.

Non-small cell lung cancer in China

In China,lung cancer is a primary cancer type with high incidence and mortality.Risk factors for lung cancer include tobacco use,family history,radiation exposure,and the presence of chronic lung diseases.Most early-stage non-small cell lung cancer(NSCLC)patients miss the optimal timing for treatment due to the lack of clinical presentations.Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China.The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC,thus prolonging survival in patients with positive drivers.In the exploration of immune escape mechanisms,programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China.In the Chinese Society of Clinical Oncology’s guidelines for NSCLC,maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy.Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC.In this review,we summarized recent advances in NSCLC in China in terms of epidemiology,biology,molecular pathology,pathogenesis,screening,diagnosis,targeted therapy,and immunotherapy。

Immune checkpoint:The novel target for antitumor therapy

Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).