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Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan–Meier approach. Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS -mutated (NRAS mut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33–47] in NRAS mut patients and 41% [95% CI, 35–48] in NRAS -wild type (NRAS wt) patients; 2-year OS was 54% [95% CI, 48–61] in NRAS mut patients and 57% [95% CI, 50–64] in NRAS wt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44–66] in NRAS mut patients and 53% [95% CI, 41–67] in NRAS wt patients; 2-year OS was 58% [95% CI, 49–70] in NRAS mut patients and 62% [95% CI, 51–75] in NRA Swt patients). The ORR to anti-PD1 was 35% for NRAS wt patients and 26% for NRAS mut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (> 5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRAS wt and NRAS mut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status. • PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. • Similar response rates to anti-PD1-based ICI were seen for NRAS mut and NRAS wt patients. • There was no correlation between NRAS mutation status and programmed cell death ligand-1 expression. [ABSTRACT FROM AUTHOR]

Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies. This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS [95%CI] was measured using Kaplan–Meier Analysis and Log–Rank test. Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.1[2.4–7.8] months]) compared to LDHlowLM-patients (median OS: 15.3[8.9-NA] months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.8[17.9-NA] months (vs 13.1[10.8–18.5], P = 0.02) in the overall population and 30.3[19.93-NA] months (vs 14.1[8.69-NA], P = 0.0013) in patients with melanoma. LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need. • A baseline machine learning-derived signature predicted survival on immunotherapy. • LDHhi (elevated serum LDH) and LM+ (liver metastasis) forecasted short survival. • LDHlow LM-forecasted longer survival with immunotherapy than other systemic therapies. • LDH LM status could guide clinical decision making for advanced cancer patients. [ABSTRACT FROM AUTHOR]

The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities. • Sodium exhibits a linear correlation with survival in immunotherapy-treated patients • This correlation is not present for other serum electrolytes • The effect is significant in immunotherapy-treated patients only • High sodium identifies patients who profit from immunotherapy [ABSTRACT FROM AUTHOR]

The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers. The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs). 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27−85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1–17.9), median OS was 16.1 months (95% CI, 14.4–18.8) and PFS was 9.9 months (95% CI, 8.8–11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6–17.1). ORR was 43.4% (95% CI, 40.4–46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%). First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study. [Display omitted] • Chemo-immunotherapy is the standard front-line treatment for advanced non-squamous NSCLC. • Real-world data about platinum, pemetrexed and pembrolizumab regimen are needed. • We conducted a retrospective-prospective real-world study in 33 Italian Centers. • KEYNOTE-189 regimen was effective and safe in daily clinical practice. [ABSTRACT FROM AUTHOR]

Metastatic melanoma (MM) is commonly treated with a combination of nivolumab and ipilimumab, regardless of tumor PD-L1 expression. We conducted a population-based study including all patients with MM (except ocular melanoma) treated in Denmark with first-line combination therapy or anti-PD-1 monotherapy since January 2017. Baseline data including known prognostic characteristics were used in multivariable and propensity-matched score (PMS) analyses to assess progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) according to PD-L1 expression. We identified 1341 eligible patients, with known PD-L1 status for 1081 patients (43% PD-L1 ≥ 1%, 57% PD-L1 < 1%). PD-L1 ≥ 1% was an independent positive prognostic biomarker for survival in the overall cohort (MSS: HR 0.66, CI 0.52–0.83, p < 0.001). In the PMS PD-L1 ≥ 1% cohort, combination therapy showed similar clinical outcomes to monotherapy (PFS: HR 1.41, CI 0.94–2.11, p = 0.101; MSS: HR 1.21, CI 0.70–2.11, p = 0.49; OS: HR 1.17, CI 0.68–2.00, p = 0.567). In contrast, in the PMS PD-L1 < 1% and in the PMS PD-L1 < 1% BRAF WT cohorts, combination therapy improved PFS (respectively with HR 0.70, CI 0.53–0.93, p = 0.013; and HR 0.54, CI 0.37–0.78, p = 0.001), but did not reach statistically significant improvements of MSS (HR 0.72, CI 0.50–1.02, p = 0.065; and HR 0.79, CI 0.51–1.21, p = 0.278) or OS (HR 0.78, CI 0.56–1.08, p = 0.135; and HR 0.81, CI 0.54–1.21, p = 0.305) compared to monotherapy. Our findings support previous exploratory analyses of Checkmate-067, highlighting that improved clinical outcomes with combination therapy are not established in unselected patients with high (≥1%) tumor PD-L1 expression. • PD-L1 ≥ 1% is an independent positive prognostic biomarker in metastatic melanoma • PD-L1 ≥ 1% did not derive additional benefit from anti-CTLA-4 over anti-PD-1 alone • Combination therapy demonstrated improved PFS only in patients with PD-L1 < 1% [ABSTRACT FROM AUTHOR]

Platinum-based combination chemotherapy is the standard treatment for patients with chemotherapy-eligible metastatic urothelial carcinoma (mUC). Immune-checkpoint inhibitors (ICIs) are currently assessed in this setting. This review aimed to assess the role of ICIs alone or in combination as first-line treatment in chemotherapy-eligible patients with mUC. Multiple databases were searched for articles published until November 2020. Studies were deemed eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), durations of response (DORs) and adverse events (AEs) in chemotherapy-eligible patients with mUC. Three studies met our eligibility criteria. ICI combination therapy was associated with significantly better OS and PFS, higher CRR and longer DOR than chemotherapy alone (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.76–0.94, P = 0.002; HR: 0.80, 95% CI: 0.71–0.90, P = 0.0002; odds ratio [OR]: 1.48, 95% CI: 1.12–1.96, P = 0.006; and mean difference: 1.39, 95% CI: 0.31–2.46, P = 0.01, respectively). ICI-chemotherapy combination therapy was also associated with significantly better OS and PFS, higher ORR and CRR and longer DOR than chemotherapy alone. Although OS and PFS benefits of ICI combination therapy were larger in patients with high expression of programmed death-ligand 1 (PD-L1), PD-L1 low expression patients also had a benefit; HR for OS (high PD-L1: HR 0.79 versus low PD-L1: HR 0.89) and PFS (high PD-L1: HR 0.74 versus low PD-L1: HR 0.82). ICI monotherapy was not associated with better oncological outcomes but was associated with better safety outcomes than chemotherapy alone. Our analysis indicates a superior oncologic benefit to first-line ICI combination therapies in patients with chemotherapy-eligible mUC over standard chemotherapy. In contrast, ICI monotherapy was associated with favorable safety outcomes compared with chemotherapy but failed to show its superiority over chemotherapy in oncological benefits. PD-L1 status alone cannot help guide treatment decision-making. However, caution should be exercised in interpreting the conclusions drawn from this study, given that there is the heterogeneity of the population of interest, risk of bias and the nature of the studies evaluated whose data remain immature or unpublished. • ICIs are currently assessed for patients with chemotherapy-eligible mUC. • ICIs used in combination are superior to chemotherapy in oncological benefits. • ICI monotherapy efficacy is not superior to that of chemotherapy alone. • PD-L1 alone is not a sufficiently robust, reliable and reproducible biomarker. • The analyses include the heterogeneity of the population and risk of bias. [ABSTRACT FROM AUTHOR]

About 40% of patients with non-small cell lung cancer (NSCLC) develop brain metastases (BMs) throughout the disease, and the occurrence of BMs is considered to have a fairly high mortality rate. Therefore, the management of brain metastases in NSCLC patients is a clinical challenge. Currently, multidisciplinary diagnosis and treatment methods are often used to achieve effective control of intracranial disease and prolong survival. Immunotherapy (IT) is one of the core therapies for NSCLC. Single or combined IT represented by immune checkpoint inhibitors(ICIs) of programmed death-1(PD-1)/ programmed cell death-ligand 1 (PD-L1) can significantly improve the prognosis of patients with advanced NSCLC.ICIs has been shown to be safe and effective in patients with BMs, although patients with BMs are mostly underrepresented in randomized clinical trials. In this review, we summarized the mechanism of ICIs in the treatment of BMs, and the clinical research and treatment progress of ICIs and their combination with other therapies in patients with BMs s from NSCLC. [ABSTRACT FROM AUTHOR]

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC. [Display omitted] • Breast pathologists face challenges in determining PD-L1 CPS score. • Lack of standardization across assays/staining platforms for PD-L1 CPS. • Validation and harmonization of the PD-L1 assays is crucial for consistent results. • Digital pathology may be of help, providing guidelines. • Infrastructures are present but challenges persist: harmonization, training. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors are effective in recurrent/metastatic nasopharyngeal cancer (R/M NPC). RATIONALE-309 (NCT03924986) randomized 263 treatment-naive R/M NPC patients to tislelizumab or placebo every 3 weeks (Q3W), plus chemotherapy (Q3W for 4–6 cycles). At interim analysis, progression-free survival (PFS) was significantly longer with tislelizumab-chemotherapy versus placebo-chemotherapy (hazard ratio: 0.52; 95% confidence interval: 0.38, 0.73; p < 0.0001). PFS benefit for tislelizumab-chemotherapy versus placebo-chemotherapy was observed regardless of programmed death-ligand 1 expression. PFS after next line of treatment and overall survival showed favorable trends for tislelizumab-chemotherapy versus placebo-chemotherapy. The safety profile was similar between arms. Gene expression profiling (GEP) identified immunologically "hot" tumors, and showed an activated dendritic cell (DC) signature was associated with tislelizumab-chemotherapy PFS benefit. Our results support that tislelizumab-chemotherapy should be considered as first-line treatment for R/M NPC, and GEP and activated DC signature results may help identify patients who might benefit most from immunochemotherapy treatment. [Display omitted] [Display omitted] • First-line tislelizumab plus chemotherapy improves PFS, PFS2, and OS • The combination shows a manageable safety profile in patients with R/M NPC • Efficacy is observed irrespective of EBV level and PD-L1 expression • Patients with high levels of activated dendritic cell signature may benefit most from treatment Yang et al. demonstrate the efficacy and safety of tislelizumab plus chemotherapy (gemcitabine-cisplatin) in treatment-naive patients with recurrent/metastatic nasopharyngeal cancer. Compared with placebo-chemotherapy, tislelizumab-chemotherapy extends progression-free survival, irrespective of PD-L1 expression, as well as progression-free survival after next line of treatment, with a tolerable safety profile. [ABSTRACT FROM AUTHOR]

• The combination of ICIs and chemotherapy may provide better efficacy for patients with mUC. • For patients who are not suitable for platinum-based chemotherapy or fail after platinum-based chemotherapy, immunotherapy may be an appropriate treatment. • Hitherto, there are no effective markers to predict the efficacy of ICIs. Urothelial carcinoma (UC) is a very common malignant tumor. In the past few decades, platinum-based chemotherapy has been regarded as the standard recommended regimen for patients with metastatic urothelial carcinoma (mUC) who can receive either cisplatin or carboplatin. The emergence of immune checkpoint inhibitors (ICIs) brought some hope for possible treatments for mUC patients who were unfit for platinum therapy. ICIs drugs have emerged as new potential weapons to overcome UC in our lifetime. ICIs block the binding of programmed death-1 (PD-1) to programmed death-ligand 1 (PD-L1), leading to enhancement of the immune function of antitumor T cells. In the treatment of UC, ICIs show an apparent ascendancy and effectively enhance survival rates. With good tolerability and remarkable effects, ICIs have given thousands of patients hope. This article mainly shows the application of PD-1 and PD-L1 inhibitors in mUC. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) expression in pulmonary adenocarcinomas (pADCs) was implicated in predicting anti-PD-1/PD-L1 therapy efficacy. However, the differential expression of PD-L1 between primary and metastatic pADC remains unclear. Thus, we addressed this issue. In total, 161 paired primary and metastatic tumour tissues from 146 patients with pADC were collected. Most of the cases had regional nodal metastasis (134/161, 83.2%). PD-L1 expression was categorised based on the proportion of immunostained tumour cells using cutoff values of 1%, 5%, 10% and 50%. In primary tumours, PD-L1 positivity was observed in 28.1% (41/146), 27.4% (40/146), 22.6% (33/146) and 13.0% (19/146) of cases using cutoff values of 1%, 5%, 10% and 50%, respectively. The overall concordance rate for PD-L1 expression between primary and metastatic tumours was 75.2% (121/161). The concordance rate in primary tumours expressing PD-L1 in <1% or ≥50% of tumour cells was 87.2% (102/117) or 70% (14/20), respectively. In contrast, the concordance rate in tumours expressing PD-L1 in ≥1% to <50% of cells was only 20.8% (5/24). After dichotomising the cases using cutoff values of 1% and 50%, the concordance rate increased to 80.1% (129/161) and 90.7% (146/161) in all paired cases and to 70.4% (19/27) and 85.2% (23/27) in cases with distant metastases, respectively. This study demonstrates that the concordance of PD-L1 expression between primary and metastatic pADC is high when using cutoff values of 1% and 50%. Thus, evaluation of PD-L1 in either primary or metastatic tumours would be helpful for guiding anti–PD-1/PD-L1 immunotherapy in patients with advanced pADC. [ABSTRACT FROM AUTHOR]

Introduction: For cisplatin-ineligible patients, approval of first-line immune-checkpoint inhibitor therapy relies on the programmed death ligand 1 (PD-L1) expression assay employed, namely, the combined positive score (CPS) or immune cell (IC) score. This study compares PD-L1 diagnostic scores and positivity in primary and matched metastatic bladder cancer tissue.Methods: A total of 108 patients undergoing radical cystectomy for urothelial bladder cancer and lymphatic spread (pN+) were included. PD-L1 expression was compared by immunohistochemistry (IHC) between the primary bladder tumor and associated lymph node metastases using Ventana SP263 anti-PD-L1 antibody. In a subset of cases further IHC was performed with Ventana SP142 and Dako 22C3 antibodies. Second, the PD-L1 scoring algorithms for the CPS and IC score were compared. Correlation of PD-L1 positivity with clinical parameters and tumor stage was assessed. Intra- and intertissue analyses were performed with Pearson's chi square test, McNemar test and Spearman correlation employing IBM SPSS 25.Results: PD-L1 expression did not correlate with clinicopathological parameters. The CPS (43.5% vs. 35.6%; P=0.006) and the IC score (28.7% vs. 21.2%; P=0.002) yielded PD-L1 positivity significantly more often in primary BC than in matched lymph node metastasis. Both the CPS (r=0.775; P<0.001) and the IC score (r=0.711; P<0.001) correlated between primary and metastatic bladder cancer tissue. Employing CPS vs. IC led to significantly more PD-L1-positive classified cases in primary BC (CPS vs. IC; 43.5% vs. 28.7%; P<0.001) and lymph node metastasis (CPS vs. IC; 35.6% vs. 21.2%, P<0.001).Conclusion: Compared to lymph node analysis, bladder tissue yields more PD-L1 positivity assessed with the CPS and IC scores. This is particularly evident when employing the CPS. The findings highlight that employing both PD-L1 assays may maximize eligibility for first-line checkpoint-inhibitors to treat bladder cancer patients unfit for cisplatin-based chemotherapy. [ABSTRACT FROM AUTHOR]

T-cell based immune response can attack cancer cells formidably when certain immune checkpoint (e.g. , PD-1/PD-L1) is blocked. Unfortunately, PD-1/PD-L1 blockade only provoke limited immune response because the differentiation of tumor-reactive T lymphocytes is often suppressed by TGF-β pathway. Namely, the combating cancer weapon is weakened. In this study, other than employing photothermal therapy (PTT) to eliminate the primary tumor, we also aimed to expose in situ tumor-associated antigens and exert immune response for metastases inhibition. This enhanced immunotherapeutic strategy is achieved by IR780/SB-505124 based nanoliposomes (Nano-IR-SB@Lip). Upon administration, TGF-β pathway is inhibited by SB to drive effector T cells into a responsive state and reduce the infiltration of Treg cells, eventually greatly enhancing the weapon against cancer. In the meantime, the immunosuppressive "protection" of tumor cells is also neutralized by blocking PD-1/PD-L1 immune checkpoint. By virtue of inherent characteristics of IR780, Nano-IR-SB@Lip can selectively accumulate, penetrate deeply in tumor tissues, and preferentially retain in mitochondria. The above features are of critical importance to tumor therapy. Thus, highly effective cancer immunotherapy is implemented via selective accumulation/deep penetration of Nano-IR-SB@Lip in tumor, achieving PTT induced immunogenic cell death and dual mitigation of immunosuppression strategy (TGF-β inhibition/PD-1/PD-L1 blockade), which is a promising therapeutic modality for cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

• Canine Osteosarcoma expresses immune checkpoint ligands, PD-L1, B7-H3, and HVEM. • Immune checkpoint ligand expression correlates with tumor metastasis. • Immune checkpoint ligands correlate with T cell expression. • Greater resistance to T cell infiltration is seen in metastasis and tumors with higher expression of PD-L1 and/or HVEM. Immune-targeted therapies are being successfully implemented into cancer clinical practice. In particular checkpoint inhibitors are employed to modulate the immune microenvironment of solid tumors. We sought to determine the expression of PD-L1, HVEM, and B7H3 in human and canine osteosarcoma, and correlate expression with clinical features and tumor infiltrating lymphocytes in naturally-occurring canine osteosarcoma. Flow cytometry was used to measure ligand surface expression of five human and three canine cell lines. Immunohistochemistry was utilized for expression of ligands and lymphocyte markers in thirty-seven treatment-naïve canine osteosarcoma patients. All cell lines expressed all three ligands at variable levels in both species. Metastatic lesions were associated with higher expression of all three ligands in patient tumor samples. PD-L1 expression strongly correlated with B7H3 and HVEM expression, while HVEM and B7H3 were weakly correlated. Whereas peritumoral T-cell expression positively correlated with PD-L1 and HVEM tumor expression, the presence of T-cells intratumorally were rare. Furthermore, intratumor penetration by T-cells was greatest in metastatic lesions, despite log-fold increases in peritumoral T-cells. In summary, PD-L1, HVEM, and B7H3 are expressed in osteosarcoma, with metastatic disease lesions expressing higher levels. We show for the first time that these ligands expressed on osteosarcoma cells positively correlate with each other and the presence of peritumoral T cell infiltration. Furthermore, osteosarcoma appears to be an intratumoral immune desert with significant resistance to effector T cells. Multiple agents targeting checkpoints are in clinical practice, and may have immune modulating benefit in osteosarcoma. [ABSTRACT FROM AUTHOR]

Carcinosarcoma of the gynecological tract is a rare tumor with a dismal prognosis. Its immune micro-environment has not been sufficiently studied. To study the immune micro-environment of gynecological carcinosarcomas. Sixty-nine surgical specimens from 37 different patients, including 34 primary tumors and 35 metastases, were immunohistochemically studied for the expression of CD3, PD-L1, and CTLA-4. Clinical and histological features were recorded and correlated with immunohistochemical factors. Twenty-two cases involved the uterine corpus, 1 the uterine cervix, and 14 the adnexa. The overall survival ranged from 2 to 156 months, with a median survival of 16 months. CD3 expression was more frequent at the sarcomatous than the carcinomatous component. CTLA-4 expression was higher at the carcinomatous than the sarcomatous component. PD-L1 was negative in all cases studied. Tumor relapse, metastasis presence, metastasis localization, and overall survival did not correlate with CD3 or CTLA-4 expression. PD-L1 expression is not a feature of gynecological carcinosarcomas, despite a relatively frequent lymphocytic reaction. CTLA-4 expression is sometimes found in these tumors. [ABSTRACT FROM AUTHOR]