High PD-L1 Research Articles

Tumor immune microenvironment in odontogenic carcinomas: Evaluation of the therapeutic potential of immune checkpoint blockade.

Despite recent advances in the use of immune checkpoint blockade (ICB) across various cancer types, its efficacy in odontogenic carcinomas remains unexplored. This study aims to investigate PD-L1 expression and the tumor immune microenvironment (TIME) in odontogenic carcinomas to determine the therapeutic potential of ICB and the significance of immune markers. The expressions of PD-L1 and T cell markers (CD3, CD8, and FOXP3) were visualized by immunohistochemistry in 21 tissue samples of odontogenic carcinomas. Tumoral PD-L1 expression and the density and spatial distribution of T cell subsets were evaluated, from which TIME was determined. The associations of the variables with clinicopathological and prognostic factors were statistically analyzed. PD-L1 was positively expressed in 52.4% (11/21) of the cases studied. Among tumor types, ameloblastic carcinoma showed significantly higher PD-L1 expression (p = 0.016). TIME based on the intratumoral and stromal T cell distribution was immune-inflamed in 61.9% (13/21) and immune-excluded in 38.1% (8/21), with no immune-desert cases. PD-L1 expression was associated with the densities of all intratumoral T cell subsets (p = 0.03 for CD3, p = 0.03 for CD8, and p = 0.008 for FOXP3) but not with those of stromal T cells. High PD-L1 expression was associated with larger tumor size (p = 0.021), while the intratumoral CD8/CD3 ratio was inversely correlated with tumor size (p = 0.048). These findings indicate the involvement of adaptive immune resistance in a subset of odontogenic carcinomas and support the therapeutic potential of ICB in patients with these rare malignancies.

XIAP overexpressing inflammatory breast cancer patients have high infiltration of immunosuppressive subsets and increased TNFR1 signaling targetable with Birinapant

ObjectiveTo assess the expression pattern of X-linked inhibitor of apoptosis protein (XIAP), a cellular stress sensor, and delineate the associated changes in the tumor immune microenvironment (TiME) for prognostic value and new therapeutic targets in inflammatory breast cancer (IBC). MethodsImmunohistochemistry was conducted to assess the spatial localization of immune subsets, XIAP, and PDL1 expression in IBC and non-inflammatory breast cancer (nIBC) pretreatment tumors (n = 142). Validation and further exploration were performed by gene expression analysis of patient tumors along with signaling studies in a co-culture model. ResultsHigh XIAP in 37/81 IBC patients correlated significantly with high PD-L1, increased infiltration of FOXP3+ Tregs, CD163+ tumor-associated macrophages (TAMs), low CD8/CD163 ratio in both tumor stroma (TS) and invasive margins (IM), and higher CD8+ T cells and CD79α+ B cells in the IM. Gene set enrichment analysis identified cellular stress response- and inflammation-related genes along with tumor necrosis factor receptor 1 (TNFR1) expression in high-XIAP IBC tumors. Induction of TNFR1 and XIAP was observed when patient-derived SUM149 IBC cells were co-cultured with human macrophage-conditioned media simulating TAMs, further demonstrating that the TNF-α signaling pathway is a likely candidate governing TAM-induced XIAP overexpression in IBC cells. Finally, addition of Birinapant, a pan IAP antagonist, induced cell death in the pro-survival cytokine-enriched conditions. ConclusionUsing immunophenotyping and gene expression analysis in patient biospecimens along with in silico modeling and a preclinical model with a pan-IAP antagonist, this study revealed an interplay between increased TAMs, TNF-α signaling, and XIAP activation during (immune) stress in IBC. These data demonstrate the potential of IAP antagonists as immunomodulators for improving IBC therapeutic regimens.

A314 UNDIFFERENTIATED PANCREATIC CARCINOMA WITH OSTEOCLAST-LIKE GIANT CELLS: A CASE REPORT

Abstract Background Pancreatic undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) is a rare form of pancreatic cancer representing under 1% of cases. UCOGC is hypothesized to be a variant of pancreatic adenocarcinoma and while the pathophysiology is incompletely defined, it is felt to be an undifferentiated sarcomatoid carcinoma variant with chemotaxis of osteoclastic giant cells. Clinical, radiographic, or biochemical features do not reliably differentiate this from other tumors. Definitive diagnosis is made by histologic examination demonstrating non-neoplastic multinucleated osteoclastic giant cells (CD68 positive), mononuclear histiocytes, and neoplastic mononuclear cells. Aims To describe the case of a patient with UCOGC, highlighting key clinicopathologic features and management. Methods Case report and literature review. Results A 79-year-old man with atrial fibrillation on Xarelto presented with 4 months of abdominal pain, nausea, vomiting, and weight loss (22 kg). An MRI revealed a dilated main pancreatic duct and side branches with abrupt cutoff in the neck due to an ill-defined lesion. Endoscopic ultrasound confirmed a 36 mm hypoechoic ill-defined mass in the pancreatic neck. Biopsy performed with a 22-gauge needle with dry suction showed tissue fragments consistent with UCOGC (Figure 1). Unfortunately, the patient presented to hospital with worsened abdominal pain and nausea and was found to have new portal, superior mesenteric, and splenic vein thrombosis. His anticoagulant was changed to Dalteparin. A multidisciplinary cancer conference was held including input from experts in Toronto, and due to surrounding inflammation and new thrombosis he was not considered a surgical candidate at the time and neoadjuvant treatment with standard adenocarcinoma chemotherapy was planned. Unfortunately, the patient continued to decline and he was treated with palliative intent FOLFIRINOX for 2 cycles before opting for a medical assistance in dying procedure. Conclusions Treatment for UCOGC has not been well studied due to its rarity. Surgery is first-line therapy if appropriate based on patient status and cancer stage. The efficacy of chemotherapy and radiation is unclear but as a suspected adenocarcinoma variant, standard chemotherapy regimens are often used. Research is ongoing with an area of interest being PD-L1 inhibition due to high tumor PD-L1 positivity rates. Recognition of this rare entity is crucial due to its distinct diagnostic and therapeutic characteristics with more research needed to establish optimal therapy. Figure 1: Pathologic examination with HPS and CD68 stains demonstrating UCOGC Funding Agencies None

Distinct profiles of proliferating CD8+/TCF1+ T cells and CD163+/PD-L1+ macrophages predict risk of relapse differently among treatment-naïve breast cancer subtypes

Immunophenotypic analysis of breast cancer microenvironment is gaining attraction as a clinical tool improving breast cancer patient stratification. The aim of this study is to evaluate proliferating CD8 + including CD8 + TCF1 + Τ cells along with PD-L1 expressing tissue-associated macrophages among different breast cancer subtypes. A well-characterized cohort of 791 treatment-naïve breast cancer patients was included. The analysis demonstrated a distinct expression pattern among breast cancer subtypes characterized by increased CD8 + , CD163 + and CD163 + PD-L1 + cells along with high PD-L1 status and decreased fraction of CD8 + Ki67 + T cells in triple negative (TNBC) and HER2 + compared to luminal tumors. Kaplan–Meier and Cox univariate survival analysis revealed that breast cancer patients with high CD8 + , CD8 + Ki67 + , CD8 + TCF1 + cells, PD-L1 score and CD163 + PD-L1 + cells are likely to have a prolonged relapse free survival, while patients with high CD163 + cells have a worse prognosis. A differential impact of high CD8 + , CD8 + Ki67 + , CD8 + TCF1 + T cells, CD163 + PD-L1 + macrophages and PD-L1 status on prognosis was identified among the various breast cancer subtypes since only TNBC patients experience an improved prognosis compared to patients with luminal A tumors. Conversely, high infiltration by CD163 + cells is associated with worse prognosis only in patients with luminal A but not in TNBC tumors. Multivariate Cox regression analysis in TNBC patients revealed that increased CD8 + [hazard ratio (HR) = 0.542; 95% confidence interval (CI) 0.309–0.950; p = 0.032), CD8 + TCF1 + (HR = 0.280; 95% CI 0.101–0.779; p = 0.015), CD163 + PD-L1 + (HR: 0.312; 95% CI 0.112–0.870; p = 0.026) cells along with PD-L1 status employing two different scoring methods (HR: 0.362; 95% CI 0.162–0.812; p = 0.014 and HR: 0.395; 95% CI 0.176–0.884; p = 0.024) were independently linked with a lower relapse rate. Multivariate analysis in Luminal type A patients revealed that increased CD163 + was independently associated with a higher relapse rate (HR = 2.360; 95% CI 1.077–5.170; p = 0.032). This study demonstrates that the evaluation of the functional status of CD8 + T cells in combination with the analysis of immunosuppressive elements could provide clinically relevant information in different breast cancer subtypes.

Cabozantinib plus pembrolizumab as first-line therapy for cisplatin-ineligible advanced urothelial carcinoma (PemCab).

539 Background: Pembrolizumab (pem) was initially approved in the first line setting for cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients (pts) with high PD-L1 expression and platinum ineligible pts regardless of PD-L1 status; this later changed to only platinum ineligible pts. There is a high disease progression (PD) rate with pem monotherapy. Cabozantinib (cabo) is a multiple receptor tyrosine kinase inhibitor targeting MET and VEGFR2 approved in multiple other malignancies as monotherapy or in combination with PD-1 inhibition. We hypothesized that combination of pem and cabo therapy will be safe and efficacious in patients with treatment naïve mUC. Methods: This is a phase II, open label, multi-center, single arm trial evaluating the tolerability and activity of pem 200 mg every 3 weeks and cabo 40 mg daily as first-line treatment for patients with mUC. Key inclusion criteria were histologically proven locally advanced or mUC, ECOG-PS 0-2, cisplatin-ineligible (including patient refusal of cisplatin), treatment naïve, and no prior PD-1/L1 therapy. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). There was a lead-in safety cohort of 6 pts. We hypothesized that combination therapy would improve ORR to > 32%. With 35 evaluable subjects, the lower bound of the 95% confidence interval would extend no more than 26% from the observed proportion. With ≥17 objective responses, the confidence interval excludes 32%. Results: Between December 26, 2018, and April 19, 2023, 36 pts were enrolled of which 35 were evaluable for response with the median follow up of 14.4 months (95% CI 12.2 – 16.2). The median age was 72.5y [range, 47-82]; ECOG PS 0-1 in 89% pts. Responses were observed in 15 pts (ORR= 42.8%) including complete responses in 5 pts (14.3%). Stable disease was seen in 10 pts (28.6%). The disease control rate was 68.5% (25/35). Median PFS was 7.7 months (95% CI 4.2 – 11.2). Fifty-two percent of pts developed any grade treatment-related adverse events (TRAE) attributable to either cabozantinib or pembrolizumab. The most common grade 1/2 TRAE were diarrhea, anorexia, dysgeusia, weight loss, and nausea. Forty-four percent pts developed grade 3/4 TRAEs most common being hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. Conclusions: This novel phase II trial of pem + cabo demonstrated a manageable toxicity profile and promising efficacy as first-line therapy in mUC including patient’s ineligible for cisplatin. Further investigation with a focus on predictive biomarkers is ongoing. Clinical trial information: NCT03534804 .

The association of PD-L1 expression and CD8-positive T cell infiltration rate with the pathological complete response after neoadjuvant treatment in HER2-positive breast cancer.

Achieving a pathological complete response (pCR) after neoadjuvant therapy in HER2-positive breast cancer patients is the most significant prognostic indicator, suggesting a low risk of recurrence and a survival advantage. This study aims to investigate clinicopathological parameters that can predict the response to neoadjuvant treatment in HER2 + breast cancers and to explore the roles of tumour-infiltrating lymphocytes (TILs), CD8 + T lymphocytes and PD-L1 expression. This single-centre retrospective study was conducted with 85 HER2-positive breast cancer patients who underwent surgery after receiving neoadjuvant therapy between January 2017 and January 2020. Paraffin blocks from these patients were selected for immunohistochemical studies. A complete pathological response to neoadjuvant treatment was determined in 39 (45.9%) patients. High Ki-67 index (> 30%), moderate to high TIL infiltration, PD-L1 positivity and high CD8 cell count (≥ 25) were significantly associated with pCR in univariate analyses (p: 0.023, 0.025, 0.017 and 0.003, respectively). Multivariate regression analysis identified high Ki-67 index (> 30%) and CD8 cell infiltration as independent predictors for pCR in HER2-positive breast cancer. High Ki-67 index, and high CD8 cell count are strong predictors for pCR in HER2-positive breast cancer. Tumours with high Ki-67 index, high TILs and CD8 infiltration may represent a subgroup where standard therapies are adequate. Conversely, those with low TILs and CD8 infiltration may identify a subgroup where use of novel strategies, including those that increase CD8 infiltration could be applied.

Impact of PD-L1 expression on survival in patients with unresectable/recurrent gastric cancer receiving first-line chemotherapy without immune checkpoint inhibitors.

391 Background: Although high PD-L1 expression predicts a favorable response of advanced solid tumors to immune checkpoint inhibitors (ICIs), its impact on survival in patients with unresectable/recurrent gastric cancer (GC) has remained unclear. We investigated the prognostic value of PD-L1 expression for survival in unresectable/recurrent GC patients receiving first-line chemotherapy without ICIs. Methods: JCOG1013, a phase 3 randomized trial, demonstrated the addition of docetaxel to cisplatin and S-1 as first-line chemotherapy was of no benefit to patients with unresectable/recurrent GC (N=741) either for overall survival (OS) or progression-free survival (PFS). Tumor specimens prior to chemotherapy were collected for assessing PD-L1 expression for this ancillary study. PD-L1 expression was determined using immunohistochemistry (Dako, 28-8 pharmDx) and used to derive the PD-L1 combined positive score (CPS) and PD-L1 tumor proportion score (TPS). As with the CheckMate 649 study, the cutoff values for PD-L1 CPS and PD-L1 TPS were set at 5 and 1%, respectively. Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of PD-L1 CPS and PD-L1 TPS as predictors of OS and PFS. All p values were 2-sided; values <0.05 were considered statistically significant. Results: We analyzed 427 patients with unresectable/recurrent GC. The prevalence of PD-L1 CPS≥5, and PD-L1 TPS≥1% was 33% and 24%, respectively. There was no significant difference in OS and PFS between the PD-L1 CPS ≥5 group and the PD-L1 CPS <5 group (Table). The PD-L1 TPS ≥1% group had superior OS and PFS compared to the PD-L1 TPS <1% group (Table). In multivariable analyses for OS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (hazard ratio (HR) = 0.64 [95% CI: 0.50–0.83], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.82 [95% CI: 0.65–1.02], p = 0.073). In multivariable analyses for PFS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (HR = 0.67 [95% CI: 0.52–0.84], p<0.001), but PD-L1 CPS≥5 was not (HR = 0.83 [95% CI: 0.67–1.03], p = 0.090). Conclusions: PD-L1 TPS≥1% is significantly correlated with longer OS and PFS in patients with unresectable/recurrent GC receiving first-line chemotherapy without ICIs. PD-L1 TPS should be considered as a stratification factor in randomized clinical trials for unresectable/recurrent GC. Clinical trial information: UMIN000007652 . [Table: see text]

Phase II trial of cabozantinib (cabo) plus durvalumab (durva) in chemotherapy refractory microsatellite stable (MSS) patients with advanced gastric and esophageal (G/E) adenocarcinoma: CAMILLA G/E cohort results.

373 Background: Cabo is a multi-tyrosine kinase inhibitor harboring anti-VEGFR2, MET, AXL, MER and TYRO3 activity. Immunomodulatory and synergistic anti-tumor activity of cabo in combination with PD-1/L1 inhibitors have been demonstrated preclinically and in prior studies in various solid tumors. The phase Ib gastrointestinal (GI) basket CAMILLA trial evaluating cabo + durva confirmed manageable toxicity and anti-tumor activity, leading to the expansion into a multi-cohort phase 2 study. Herein, we report the results of the phase II G/E adenocarcinoma cohort. Methods: Patients (Pts) enrolled in the phase II G/E adenocarcinoma cohort were administered cabo + durva at the RP2D of 40mg QD and 1500mg IV Q4W respectively. Enrolled pts must have progressed on >1 line(s) of systemic therapy. Prior exposure to PD-1/L1 inhibitors was allowed. Those with HER2 positive disease must have progressed on anti-HER2 therapies. The primary outcome was objective response rate (ORR). Secondary outcomes were treatment-related adverse events (TRAEs), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Exploratory subgroup analyses were conducted in PD-L1 CPS >5. Results: 31 patients were enrolled, with 29 patients evaluable for efficacy. The median age was 61 years (range 32-79). 86% had an ECOG performance status of one. 48% had ≥ 2 prior lines of systemic therapies (range 1-4). Of the 29 pts evaluable for efficacy, 6 pts had confirmed objective responses (5 PR + 1 CR = ORR 20.69%). The most common TRAEs were fatigue (65%), anorexia (58%), elevated liver enzymes (39%), and diarrhea (35%). Grade >3 TRAEs occurred in 19% of pts. Grade >3 immune-related adverse events (irAE) rate was 6%. DCR was 86.2% (25/29). Median PFS and OS were 4.4 (95% confidence interval (CI) 2.2-5.4) and 5.6 months (95% CI 3.6-8.3) respectively. In patients with PD-L1 CPS >5 (12/29), ORR was 25%, and median PFS and OS were 5.5 months (95% CI 1.8-12.4) and 19.3 months (95% CI 2.3-28.2) respectively. Conclusions: Cabo + durva showed anti-tumor activity and manageable toxicity in advanced chemotherapy refractory G/E adenocarcinoma. Further evaluation in patients with high PD-L1 CPS ≥ 5 is warranted in a future randomized trial. Clinical trial information: NCT03539822 .

Immunotherapy for endocrine tumours: a clinician's perspective.

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

Uncovering immune checkpoint heterogeneity in oral squamous cell carcinoma using single cell RNA-sequencing data highlights three subgroups of patients with distinct immune phenotypes

ObjectivesIn head and neck squamous cell carcinoma (HNSCC), PD-1/PD-L1 inhibitors remain inefficient in most patients, which points to the need for better characterization of immune checkpoint (ICP) molecule expression. Material and methodsWe evaluated the expression of 22 ICP ligands (ICPL) in 2,176 malignant cells from 10 patients in a public single-cell RNA-sequencing dataset and in two cohorts of HNSCC patients for which gene expression data are available. ResultsBased on ICPL expression, malignant cells formed three distinct clusters characterized either by a strong expression of ICPL together with an immune phenotype linked to IFN-γ response (cluster 1) or by a weak ICPL expression and little response to IFN-γ (clusters 2 and 3). Malignant cells from cluster 3 showed a high PD-L1 expression associated with NRF2 signature. The relevance of 3 groups of patients, i.e “high ICPL/high IFN-γ”, “low ICPL/low IFN-γ” or “low ICPL/low IFN-γ/high PD-L1” was confirmed in a cohort of 259 OSCC whole tumor samples from TCGA and in the CLB-IHN cohort including patients treated with PD1/PD-L1 inhibitors. The heterogeneous expression of ICPL among patients’ malignant cells was associated with immunologically distinct microenvironments, evaluated with the “hot/cold” and the Tumor microenvironment (TME) classification. Finally, the “low ICPL/low IFN-γ/high PD-L1” group 3 displayed a poor prognosis in the TCGA cohort. ConclusionHence, the global picture of ICPL gene expression in malignant cells from HNSCC patients may contribute to the broader issue of improving immunotherapy strategies though a better stratification of patients and the design of new treatment combinations.

Response to PD-1 inhibitor in SMARCB1‑deficient undifferentiated rectal carcinoma with low TMB, proficient MMR and BRAF V600E mutation: a case report and literature review

Background Despite major advancements, effective treatment for patients with SMARCB1-deficient cancers has remained elusive. Here, we report the first case of a SMARCB1-deficient undifferentiated carcinoma in the rectum expressing high PD-L1 and responding to a PD-1 inhibitor, as well as with low tumor mutation burden (TMB), proficient mismatch repair (MMR) and BRAF V600E mutation.Case presentation A 35-year-old man visited our hospital complaining of increased defecation frequency, bloody stools and weight loss of 3 kg for one month. Colonoscopy revealed an ulcerated and irregular mass approximately 8–12 cm from the anus. Surgical resection was performed. Histopathological findings revealed that the tumor cells had poor connectivity with each other; each cell had eosinophilic cytoplasm and a polymorphic nucleus. Brisk mitotic activity and necrosis were frequently observed in the tumor cells. Immunohistochemical examination showed that the tumor cells were negative for SMARCB1. The tumor proportion score (TPS) of PD-L1 (22C3) expression was 95%, and the combined positive score (CPS) was 100; the tumor was mismatch repair (MMR) proficient. Next-generation sequencing showed a low tumor mutation burden (TMB), as well as the BRAF V600E mutation. The final diagnosis was SMARCB1-deficient undifferentiated carcinoma. Chemotherapy was useless in this case. His tumor recurred during chemotherapy, and he then received targeted therapy with tirelizumab, an inhibitor of PD-1. At present, his general condition is good. A recent computed tomography (CT) scan showed that the tumor had disappeared, indicating that the immunotherapy was effective. Astonishingly, his most recent follow-up was in August, and his condition continued to improve with the tumor has disappeared.ConclusionSMARCB1‑deficient undifferentiated carcinoma in the rectum is extremely rare, and it has aggressive histological malignancy and poor progression. The observed response to PD-1 inhibitors suggests a role for prospective use of SMARCB1 alterations as a predictive marker for immune checkpoint blockade.

The prognostic value of CD8+ CTLs, CD163+ TAMs, and PDL1 expression in the tumor microenvironment of primary central nervous system lymphoma

To explore immune cell infiltration and PDL1 expression in the tumor microenvironment (TME) of primary central nervous system lymphoma (PCNSL), we performed immunohistochemical staining on paraffin-embedded tumor tissues from 34 patients diagnosed with PCNSL. CD8 and CD163 positive cells were manually counted, and PDL1 expression was quantified by the H-score scoring method in the tumor center and around the tumor. The Kaplan–Meier method was used to analyze the prognostic value of the TME. We found obvious infiltration of CD8+ CTLs and CD163+ TAMs in the TME of PCNSL patients. And PDL1 was expressed in the tumor center as well as around the tumor. Survival analysis showed that high CD8+ CTLs levels and high intratumoral PDL1 expression were significantly correlated with longer OS. High CD8+ CTLs and CD163+ TAMs levels were associated with longer PFS.

Incidence of venous thromboembolism and association with PD-L1 expression in advanced non-small cell lung cancer patients treated with first-line chemo-immunotherapy.

Venous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression. We performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications. 109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death. VTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with VTE.

Early inflammatory markers as prognostic indicators following allogeneic stem cell transplantation.

Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy although graft versus host disease and relapse remain major complications. We measured the serum protein expression of 92 inflammation-related markers from 49 patients at Day 0 (D0) and 154 patients at Day 14 (D14) following transplantation and related values to subsequent clinical outcomes. Low levels of 7 proteins at D0 were linked to GvHD whilst high levels of 7 proteins were associated with relapse. The concentration of 38 proteins increased over 14 days and higher inflammatory response at D14 was strongly correlated with patient age. A marked increment in protein concentration during this period associated with GvHD but reduced risk of disease relapse, indicating a link with alloreactive immunity. In contrast, patients who demonstrated low dynamic elevation of inflammatory markers during the first 14 days were at increased risk of subsequent disease relapse. Multivariate time-to-event analysis revealed that high CCL23 at D14 was associative of AGvHD, CXCL10 with reduced rate of relapse, and high PD-L1 with reduced overall survival. This work identifies a dynamic pattern of inflammatory biomarkers in the very early post-transplantation period and reveals early protein markers that may help to guide patient management.

High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome.

CTLA-4 impedes the immune system's antitumor response. There are two Food and Drug Administration-approved anti-CTLA-4 agents - ipilimumab and tremelimumab - both used together with anti-PD-1/PD-L1 agents. To assess the prognostic implications and immunologic correlates of high CTLA-4 in tumors of patients on immunotherapy and those on non-immunotherapy treatments. We evaluated RNA expression levels in a clinical-grade laboratory and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors, including 489 patients with advanced/metastatic cancers and full outcome annotation. A reference population (735 tumors; 35 histologies) was used to normalize and rank transcript abundance (0-100 percentile) to internal housekeeping gene profiles. The most common tumor types were colorectal (140/514, 27%), pancreatic (55/514, 11%), breast (49/514, 10%), and ovarian cancers (43/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (⩾75th percentile rank). Cancers with the largest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). High CTLA-4 RNA independently/significantly correlated with high PD-1, PD- L2, and LAG3 RNA levels (and with high PD-L1 in univariate analysis). High CTLA-4 RNA expression was not correlated with survival from the time of metastatic disease [N = 272 patients who never received immune checkpoint inhibitors (ICIs)]. However, in 217 patients treated with ICIs (mostly anti-PD-1/anti-PD- L1), progression-free survival (PFS) and overall survival (OS) were significantly longer among patients with high versus non-high CTLA-4 expression [hazard ratio, 95% confidence interval: 0.6 (0.4-0.9) p = 0.008; and 0.5 (0.3-0.8) p = 0.002, respectively]; results were unchanged when 18 patients who received anti-CTLA-4 were omitted. Patients whose tumors had high CTLA-4 and high PD-L1 did best; those with high PD-L1 but non-high CTLA-4 and/or other expression patterns had poorer outcomes for PFS (p = 0.004) and OS (p = 0.009) after immunotherapy. High CTLA-4, especially when combined with high PD-L1 transcript expression, was a significant positive predictive biomarker for better outcomes (PFS and OS) in patients on immunotherapy.

TIM-3 transcriptomic landscape with clinical and immunomic correlates in cancer.

TIM-3, an inhibitory checkpoint receptor, may invoke anti-PD-1/anti-PD-L1 immune checkpoint inhibitor (ICI) resistance. The predictive impact of TIM-3 RNA expression in various advanced solid tumors among patients treated with ICIs is yet to be determined, and their prognostic significance also remains unexplored. We investigated TIM-3 transcriptomic expression and clinical outcomes. We examined TIM-3 RNA expression data through the OmniSeq database. TIM-3 transcriptomic patterns were calibrated against a reference population (735 tumors), adjusted to internal housekeeping genes, and calculated as percentiles. Overall, 514 patients (31 cancer types; 489 patients with advanced/metastatic disease and clinical annotation) were assessed. Ninety tumors (17.5% of 514) had high (≥75th percentile RNA rank) TIM-3 expression. Pancreatic cancer had the greatest proportion of TIM-3 high expressors (36% of 55 patients). Still, there was variability within cancer types with, for instance, 12.7% of pancreatic cancers harboring low TIM-3 (<25th percentile) levels. High TIM-3 expression independently and significantly correlated with high PD-L2 RNA expression (odds ratio (OR) 9.63, 95% confidence interval (CI) 4.91-19.4, P<0.001) and high VISTA RNA expression (OR 2.71, 95% CI 1.43-5.13, P=0.002), all in multivariate analysis. High TIM-3 RNA did not correlate with overall survival (OS) from time of metastatic disease in the 272 patients who never received ICIs, suggesting that it is not a prognostic factor. However, high TIM-3 expression predicted longer median OS (but not progression-free survival) in 217 ICI-treated patients (P=0.0033; median OS, 2.84 versus 1.21 years (high versus not-high TIM-3)), albeit not retained in multivariable analysis. In summary, TIM-3 RNA expression was variable between and within malignancies, and high levels associated with high PD-L2 and VISTA checkpoints and with pancreatic cancer. Individual tumor immunomic assessment and co-targeting co-expressed checkpoints merits exploration in prospective trials as part of a precision immunotherapy strategy.

Evaluating the Clinical Characteristics and Prognosis of Advanced Non-Small Cell Lung Cancer with Exon 20 Insertions.

Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins), an uncommon mutation in non-small cell lung cancer (NSCLC), can induce poor patient response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the clinical features and prognosis of patients with EGFR ex20ins are not clearly understood. This study investigated the clinical characteristics and prognosis of advanced NSCLC patients with EGFR ex20ins. Advanced NSCLC patients treated at Fujian Cancer Hospital were consecutively recruited from June 1, 2014 to December 20, 2021 and retrospectively examined. EGFR ex20ins was identified by polymerase chain reaction (PCR) or next-generation sequencing (NGS). The clinical characteristics, treatment methods, and patient outcomes were retrieved from the hospital database. The progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. Fourteen mutation subtypes of EGFR ex20ins were identified in the 24 enrolled patients, with EGFR ex20ins mutation more prevalent in non-smoking women. A763_Y764insFQEA and A767_V769dup (12.5% for both) were the most common mutation subtypes. Notably, no significant differences in PFS and OS were found between the first-line targeted therapy group [PFS: 257 days, 95% confidence interval (CI): 116-397 days; OS: not reached] and chemotherapy-based combination therapy group (PFS: 182 days, 95% CI: 156-207 days; OS: 998 days, 95% CI: 674-1321 days). TP53 mutation was the commonest concomitant mutation (62%), followed by EGFR amplification (25%). Chemotherapy combined with immunotherapy improved the prognosis of patients with high PD-L1 expression. For NSCLC patients with EGFR ex20ins, limited therapeutic benefits can be gleaned from either EGFR-TKIs or chemotherapy-based combination therapy.

Soy isoflavone genistein attenuates the efficacy of immune checkpoint therapy in C57BL/6 mice inoculated with B16F1 melanoma and a high PD-L1 expression level reflects tumor resistance.

Immune checkpoint therapy has been shown to be an effective therapy for many types of tumors. Much attention has been paid to the development of an effector target would be helpful for immune checkpoint therapy. Genistein has been shown to have an anti-tumor effect both in vitro and in vivo. In this study, we examined the effect of genistein on immune checkpoint blockade therapy against B16F1 melanoma tumors. Mice treated with genistein or anti-programmed death (PD)-1 antibody showed a significant decrease in tumor growth. However, treatment with genistein had no effect on or attenuated the efficacy of immune checkpoint therapy. The percentages of T cell receptor (TCR)β+CD4+ and TCRβ+CD8+ cells and the concentrations of interferon-γ and tumor necrosis factor-α in tumor tissue were not different among the experimental groups. A significant difference was also not found in microbe composition. Interestingly, a high expression level of PD-ligand (L)1 closely reflected the outcome of therapy by genistein or anti-PD-1 antibody. The study showed that a combination of genistein treatment does not improve the effect of immune blockade therapy. It also showed that a high PD-L1 expression level in tumors is a good prediction maker for the outcome of tumor therapy.

PD-L1 immunohistochemical expression considering HPV status in oropharyngeal squamous cell carcinoma.

This systematic review aims to determine whether the presence of human papillomavirus (HPV) influences the immunohistochemical expression of programmed cell death-1 ligand (PD-L1) in oropharyngeal squamous cell carcinoma (OPSCC). PD-L1 immunohistochemical expression varies in OPSCC, and the presence of HPV is a plausible explanation for this variability. Comprehending these findings is crucial, as high PD-L1 expression in the tumor microenvironment of OPSCC can help identify patient subgroups that could be suitable for immunotherapy. Therefore, a systematic review was conducted following PRISMA guidelines (CRD42023437800). An electronic literature search was performed without time or language restrictions. The search included PubMed/MEDLINE, Embase, Scopus, Web of Science, https://clinictrials.gov, and relevant journals. A meta-analysis was performed using RStudio. Fourteen studies involving 1,629 participants were included. The sample consisted predominantly of males (81.26%) with a mean age of 58.3 years. Concerning clinical and pathological characteristics, the most frequently described anatomical location was the tonsils (68.54%), and most participants were either current or former smokers (78%) and alcohol users (79%). Advanced TNM IV was the most common stage. Regarding histopathological characteristics, HPV 16 was the only type mentioned, and half of the cases were detected through immunohistochemistry. The SP142 clone (35.7%) and the pattern of membrane immunostaining in tumor cells (71%) were the most commonly employed methods. The most prevalent findings were positive expression of PD-L1 (64.28%) and negative HPV status (57.14%). The association between PD-L1 positivity and HPV positivity (78.57%) was confirmed by meta-analysis. The conclusion was that HPV-positive status has an impact on immunohistochemical expression of PD-L1 in OPSCC.

Association Between Clinicopathological Parameters and S100A8/A9 Expression According to Smoking History in Patients With Non-small Cell Lung Cancer.

Lung cancer is a major cause of cancer-related deaths worldwide, and chronic inflammation caused by cigarette smoke plays a crucial role in the development and progression of this disease. S100A8/9 and RAGE are associated with chronic inflammatory diseases and cancer. This study aimed to investigate the expression of S100A8/9, HMBG1, and other related pro-inflammatory molecules and clinical characteristics in patients with non-small cell lung cancer (NSCLC). We obtained serum and bronchoalveolar lavage (BAL) fluid samples from 107 patients and categorized them as never or ever-smokers. We measured the levels of S100A8/9, RAGE, and HMGB1 in the collected samples using enzyme-linked immunosorbent kits. Immunohistochemical staining was also performed to assess the expression of S100A8/9, CD11b, and CD8 in lung cancer tissues. The correlation between the expression of these proteins and the clinical characteristics of patients with NSCLC was also explored. The expression of S100A8/A9, RAGE, and HMGB was significantly correlated with smoking status and was higher in people with a history of smoking or who were currently smoking. There was a positive correlation between serum and BAL fluid S100A8/9 levels. The expression of S100A8/A9 and CD8 in lung tumor tissues was significantly correlated with smoking history in patients with NSCLC. Ever-smokers, non-adenocarcinoma histology, and high PD-L1 expression were significant factors predicting high serum S100A8/9 levels in multivariate analysis. The S100A8/9-RAGE pathway and CD8 expression were increased in smoking-related NSCLC patients. The S100A8/9-RAGE pathway could be a promising biomarker for chronic airway inflammation and carcinogenesis in smoking-related lung diseases.