1.Prognostic Value Of TIGIT/CD47 Expression In Lung Squamous Cell Carcinoma 2.Efficacy Of Anti-PD-1/PD-L1 Neoadjuvant Immunotherapy And Surgery In Lung Squamous Cell Carcinoma

Background:In recent years,the role of immune checkpoint inhibitors in tumor treatment has become increasingly prominent and markedly shifted the therapeutic paradigm of various tumors.Currently,PD-1/PD-L1 inhibitors are the most widely used for immunotherapy.However,the response rate of PD-1/PD-L1 inhibitors to non-small cell lung cancer(NSCLC)was only 20%.Many patients still have dismal prognoses,hence the importance of finding potential immune checkpoints.The immune system plays a vital role in the antitumor response,but cancers can still progress by evading immune surveillance.The T-cell immunoreceptor with Ig and ITIM domains(TIGIT)is a coinhibitory receptor.Studies have found that TIGIT is highly expressed in colon cancer,multiple myeloma,breast cancer,prostate cancer,and so on.It is closely related to prognosis.Targeted TIGIT antibodies can effectively restore T cell function and exert antitumor effect.Studies targeting TIGIT are rare in lung squamous cell carcinoma(LUSC).Cluster of differentiation 47(CD47)is a glycoprotein widely expressed on cell surface.It plays an essential role in various cellular functions such as regulating adhesion,proliferation,axon extension,fusion,migration,phagocytosis,and apoptosis.It can block the phagocytosis of macrophages,as well as mediate the migration of neutrophils and platelet activation and diffusion by binding to signal-regulatory proteins(SIRP α).CD47 inhibitors have been used in clinical trials in ovarian cancer,colorectal cancer,and leukemia;however,lung cancer-related studies remain limited.Method:LUSC transcriptional predictive data were downloaded from The Cancer Genome Atlas(TCGA),including age,gender,and stage.The gene transcription data of TIGIT and CD47 were extracted and combined with the survival data.Data pertaining to 190 patients with LUSC from April 2006 to February 2011 were collected retrospectively.Lobectomy or pneumonectomy and systematic lymph node dissection were conducted in all patients.The postoperative staging criteria were based on the 8th Edition of TNM Staging of Lung Cancer.Data pertaining to gender,age,smoking history,mode of operation,postoperative pathology,and staging were collected retrospectively.Formalin fixed paraffin-embedded specimens of tumor tissues wereRelationship between the immune checkpoints TIGIT/CD47 expression and the prognosis of lung squamous cell carcinoma retrieved from the department of pathology of our center.TIGIT,CD47,PD-L1,and CD8 were detected via immunohistochemical staining using tissue microarrays.Results:The median follow-up period in the LUSC cohort from the TCGA database was 18.3 months(0.1-176.2 months).Survival analyses were conducted using Kaplan-Meier curves.Univariate analysis indicated that T stage,TNM stage,CD47 expression in transcription,and dual expression in transcription of TIGIT/CD47 were associated with shorter overall survival(OS)(T stage,p=0.001;TNM stage,p=0.005;CD47 transcription,p=0.022,and TIGIT/CD47 dual expression,p=0.049).Multivariate analysis confirmed that the TNM stage(p=0.006)and TIGIT/CD47 dual expression(p=0.047)were independent prognostic factors for LUSC.In the LUSC cohort of our center,the 5-year OS rate was 68.4%,with a median survival time of 65 months.In the univariate analysis,the T,N,and TNM stages;TIGIT-positive TIL density;CD47 high expression,CD47/PD-L1,TIGIT/CD47 and TIGIT/PD-L1 dual high expression were associated with shorter OS(T stage,p<0.001;N stage,p<0.001;TNM stage,p<0.001;TIGIT positive TIL density,p=0.027;CD47 expression,p=0.003;TIGIT/CD47 dual high expression,p=0.023;and TIGIT/CD47 dual high expression,p=0.020;TIGIT/PD-L1 dual high expression,p=0.039).In the multivariate analysis,advanced age,TNM stage,and TIGIT/CD47 dual high expression were independent prognostic factors for LUSC(age,p=0.001;TNM stage,p<0.001;and dual-positive TIGIT/CD47,p=0.046).Conclusion:Elevated dual expression of TIGIT/CD47,CD47/PD-L1 and TIGIT/PD-L1 were associated with poor prognosis in LUSC.These results suggest that CD47 and TIGIT may be potential immunotherapeutic targets for LUSC,especially combined immunotherapy with PD-L1/PD-1 inhibitors.However,further clinical studies are still needed to corroborate our findings.Background:As a rising star,immunotherapy has gradually come into the spotlight of lung cancer treatment,which has improved the therapeutic effect of advanced non-small-cell lung cancer(NSCLC).Immune escape has been identified as one of the main mechanisms of tumorigenesis.The interaction between immune checkpoint ligands located on tumor cells and immune checkpoint receptors on immune cells is a key component of the immune escape mechanism.Neoadjuvant therapy combined with surgical treatment plays a critical role in treating lung cancer.The neoadjuvant treatment of resectable NSCLC includes neoadjuvant chemotherapy,immunotherapy,and neoadjuvant immunochemotherapy,which can reduce the primary tumor,eliminate micrometastasis and improve the complete resection rate.The efficacy of immunochemotherapy is higher and the toxicity lower than in chemotherapy and immunotherapy of advanced NSCLC.In phase II clinical trials of resectable NSCLC,the major pathological response rate of patients treated with neoadjuvant immunotherapy was as high as 45%,twice as high as previously reported neoadjuvant chemotherapy.There is no comprehensive and systematic evaluation of the surgical challenges after neoadjuvant immunotherapy.In order to reduce the differences associated with different pathological types,this study retrospectively analyzed the surgical interventions following neoadjuvant immunotherapy for lung squamous cell carcinoma.Methods:Following neoadjuvant therapy,all the patients in this study underwent surgical treatment in the thoracic surgery department of our hospital.Chest CT examination was performed in our hospital before the first treatment.In this study,neoadjuvant therapy includes neoadjuvant immunotherapy,neoadjuvant chemotherapy,and neoadjuvant immunotherapy combined with chemotherapy.Major pathological response was defined as less than 10%of the surviving tumor cells,and complete pathological remission was defined as completed pathological response.Results:A total of 68 patients were included in this study,including 61 males(89.7%).The age range was 48 to 77 years,with a median age of 64 years;52 patients(76.5%)had a history of smoking,and 19 cases(27.9%)reported a family history of malignant tumors.There were 21 patients(30.9%)who underwent neoadjuvant chemotherapy,34 cases(50.0%)of neoadjuvant immunotherapy,and 13 cases(19.1%)of neoadjuvant immunotherapy.Thoracoscopic minimally invasive surgery was performed in 27 cases(39.7%),while 41 cases underwent open surgery;54 patients(79.4%)underwent lobectomy/combined lobectomy,and 14(20.6)underwent left pneumonectomy.The T stage of 46 patients(67.6%)decreased after treatment,including 21 cases(30.9%)with stage 0.According to the postoperative pathological report,ypTNM staging showed complete pathological remission in 15 cases(22.1%)and postoperative complications in 19 cases(27.9%).Following treatment,moderate to severe tissue changes mainly occurred in the cohort of immunotherapy and immunotherapy combined with chemotherapy(paired 0.004).The descending stage of T neoadjuvant therapy was related to tumor stage(paired 0.001).T neoadjuvant therapy resulted in complete pathological remission and correlated with age,operation mode,neoadjuvant regimen,and postoperative pathological stage(pause 0.012).The effectiveness of neoadjuvant therapy in patients over 65 years old was low.The effect of immunotherapy combined with chemotherapy was significantly better than that of chemotherapy and immunotherapy.The average duration of operation was 136.7 minutes,ranging from 50 to 289 minutes.The average postoperative hospital stay was 7.1 days,ranging from 3 to 21 days;22 patients(32.4%)were hospitalized for more than 7 days.The length of operation was related to smoking history(pause 0.027),moderate and severe treatment reactions(pause 0.010),and postoperative hospital stay(pause 0.003).Postoperative hospitalization of more than 7 days was associated with surgical procedures(paired 0.004),neoadjuvant therapy(paired 0.004),and moderate and severe tissue changes after treatment(paired 0.006).Prolonged hospital stay after pneumonectomy was longer in the neoadjuvant immunochemotherapy group than in the neoadjuvant chemotherapy group.Hospital stay after surgery was longer in the moderate and severe groups after treatment.The primary pathological remission(90%remission)was related to the mode of operation(pause 0.019),neoadjuvant therapy(pendant 0.046),N stage(pause 0.008)and postoperative pathological stage(p<0.001).Complete pathological remission(100%)was associated with surgical procedures(paired 0.029)and neoadjuvant therapy(paired 0.014).The effect of chemotherapy combined with immunotherapy was significantly better than that of immunotherapy.Conclusion:The efficacy of neoadjuvant immunotherapy combined with chemotherapy was stronger than that of immunotherapy and chemotherapy.Moderate to severe reactions after neoadjuvant therapy,such as extensive dense adhesion,and moderate and severe fibrosis or edema,were associated with longer operation time and extended hospital stays.Compared with chemotherapy alone,immunotherapy and immunochemotherapy combined with chemotherapy are more likely to cause moderate and severe reactions such as tissue edema,hilar fibrosis and vascular fragility,resulting in increased difficulty and prolonged operation time.However,the incidence of surgical complications was not increased,suggesting the safety and feasibility of surgery.