Hashimoto’s Thyroiditis Remodels Thyroid Cancer Immune Microenvironment And Its Impact On Prognosis

Objective:Hashimoto’s thyroiditis(HT)has been suggested to be associated with papillary thyroid cancer(PTC)development.However,its impact on PTC progression remains unclear.We aimed to examine the association between HT and PTC presentation and outcomes.Methods:This retrospective cohort study included a review of untreated PTC patients(1875 years)from 2001 to 2014 at our institute to examine the association between HT and PTC presentation and outcomes.Coexistent HT was defined according to postoperative paraffin sections.Logistic regression was performed to define the association between HT and clinicopathological characteristics of PTC,and then survival analysis was performed using Kaplan-Meier curves(Log-rank tests)and Cox proportional hazards model.Results:Based on the inclusion and exclusion criteria,a total of 9210 patients with PTC were analyzed.HT was present in 1751(19%)patients,which correlated negatively with frequencies of primary size≥4cm,gross extrathyroidal extension(gross ETE),extranodal extension and distant metastasis(logistic regression;adjusted OR[95%CI];0.20[0.120.33],0.44[0.36-0.54],0.66[0.55-0.80],0.17[0.04-0.71],all P<0.05).After a median follow-up of 85 months,131 PTC-related deaths were identified in the whole cohort while 2 of which had HT.Patients with HT had significantly superior outcomes compared to patients without HT in terms of unadjusted 10-year disease-specific survival(99.9%vs 96.6%,log rank P<0.01)and recurrence-free survival(92.0%vs 87.6%,log rank P<0.01)rates.After adjusting for sex,age,primary size,ETE,lymph node metastasis(LNM),distant metastasis,extent of surgery and radioactive iodine ablation,HT was associated with decreased PTC-related mortality(HR[95%CI],0.19[0.05-0.76],P=0.02).Stratified analysis shown HT was associated with less structural recurrence in patients with ETE or after total thyroidectomy(HR[95%CI],0.52[0.38-0.71],0.50[0.350.69],respectively,both p<0.001,p for interaction<0.01).Conclusions:Coexistent HT was associated with less aggressive characteristics at presentation and better outcomes of PTC.Objective:It is generally accepted that the thyroglobulin antibody(TgAb)level,which is elevated in most Hashimoto’s thyroiditis(HT)patients,can be used as a prognostic marker of PTC only after total thyroidectomy,but its value in PTC patients with concomitant HT is unclear.We aimed to assess the prognostic significance of the preoperative and early trends in postoperative serum TgAb levels in patients with concomitant PTC and HT.Methods:This retrospective cohort study included a review of untreated patients(18-75 years)who underwent thyroidectomy for PTC and pathologically proven HT from 20072016 at our institute to assess the prognostic significance of serum TgAb.The Cox proportional hazards model with restricted cubic spline was used to analyze the association between the level of serum TgAb and structural recurrence,and then survival analysis was performed using Kaplan-Meier curves(log-rank tests)and Cox proportional hazards modelResults:Based on the inclusion and exclusion criteria,a total of 839 patients enrolled.Forty-eight(5.7%)cases of recurrences were identified during a median follow-up of 64 months.Macrocarcinoma(>1 cm)and lymph node metastasis were significantly associated with higher preoperative serum TgAb levels(P=0.006,0.002),but no significant difference was found for any other clinicopathological characteristics.An increasing preoperative TgAb level up to 2000IU/ml was significantly associated with shorter recurrence-free survival(RFS)(P<0.001),and the 5-year RFS rates in patients with preoperative TgAb≤400,400-800 and>800IU/ml were 97.3%,93.2%and 85.8%,respectively(all P<0.05).A significant difference was found even after adjusting for potential risk factors(age,sex,primary tumor size,gross extrathyroidal extension,multifocality,bi laterality and LNM)(P<0.001).Of the 337 PTC patients who were treated with lobectomy and had available postoperative TgAb data at the first year after surgery,a significant decrease(≥50%)in postoperative TgAb was achieved in 41.8%of patients,who had a favorable prognosis compared with the other patients(5-year RFS rate 98.5%vs.92.0%,P=0.008).Conclusions:The preoperative and early postoperative trends of serum TgAb seem to effectively stratify patients with concomitant PTC and HT who are at high risk for recurrence.Objective:Papillary thyroid cancer(PTC)is frequently accompanied by Hashimoto’s thyroiditis(HT),and the most frequent mutation is BRAFv600E.Previous studies have indicated the prognostic role of HT or BRAFV600E in PTC patients,but few studies have focused on the tumor microenvironment(TME)alterations caused by HT and BRAFv600E or how HT and BRAFV600E cooperate to facilitate or restrict PTC progression.We aimed to assess the prognostic mechanism of HT and BRAFV600E in PTC patients.Methods:The study enrolled the following two cohort:(1)the single-cell transcriptional and T-cell receptor/B-cell receptor repertoire profiles of 19 PTC samples and adjacent normal tissues with HT+ or HT and BRAFV600E mutations.Multiplex immunohistochemistry was performed to observe the spatial location of the related cell cluster.(2)The The Cancer Genome Atlas thyroid cancer(TCGA-THCA)cohort(n=286)obtained data of HT,BRAF mutations and immunological information for analysis.Results:The BRAFv600E mutation is the key factor driving cancer cell evolution,and HT increases MHC-I antigen processing and’ presentation in cancer cells.Compared with adjacent normal tissues,tumors displayed a suppressive immune microenvironment.In PTC tumors,adaptive immune cells displayed a distinct immune infiltration spectrum across distinct HT and BRAFv600E mutation statuses.Tumors with wild-type BRAFV600E and HT had the highest infiltration levels of CD4 T follicular helper cells,B lineage cells and CXCL13+exhausted CD8 T cells(CD8Tex),which are components of tertiary lymphoid structures.We observed that CXCL13+CD8Tex exhibited high infiltration in tumor and normal adjacent tissue(NAT)of PTC with HT.According to the analysis of TCR,almost all the expanded CD8Tex clones(clone size>1)of tumor were shared with matched NATs.Precursor CD8Tex featuring NR4A2-GZMH+expressed the highest levels of several lethal effector molecules,and was the pivotal cluster of specific killing of tumor cell and TLS formationConclusions:Our analysis revealed the cellular mechanism of how HT and BRAFV600E mutation influence PTC prognosis,implicating HT and BRAFV600E mutation in optimizing the PTC classification system.