BACKGROUND: The optimal first-line therapy for metastatic renal cell carcinoma (mRCC) remains uncertain, despite recent advancements in immune-based combinations. This retrospective study compares the effectiveness of pembrolizumab plus axitinib (PA) and nivolumab plus cabozantinib (NC) as first-line treatments for mRCC in a real-world setting. METHODS: Patient data were collected from 55 centers across 16 countries, encompassing individuals diagnosed with mRCC receiving first-line treatment with PA or NC between January 2016 and October 2023. Clinical and tumor features and treatment responses were recorded. The primary endpoints were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to second progression. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazard models, and chi-square tests. RESULTS: A total of 760 patients with a median age of 64 years (range, 29-88) were included. Of them, 607 received PA, and only 153 NC. In the overall study population, ORR was 59% for and 49% for PA. Median OS was 55.7 months and not reached (NR) for PA and NC, respectively (P = .51), while median PFS was longer with NC (27.6 months) than for PA (16.2 months, P = .003). Subgroup analysis suggested a PFS benefits for NC in male, younger patients, intermediate risk group, clear cell histology, and lung involvement, as well as ORR favored NC in good risk patients. Multivariate analysis identified first-line therapy as a significant factor associated with PFS. CONCLUSIONS: In this certainly biased retrospective comparison, NC demonstrated superior ORR and longer PFS compared to PA in mRCC. These findings underscore the importance of considering individual patient characteristics and risk profiles when selecting first-line therapy for mRCC.

• Keywords
• ARON-1 study, Axitinib plus pembrolizumab, Cabozantinib plus nivolumab, Immune-oncology combinations,
• MeSH
• Anilides * therapeutic use   pharmacology   administration & dosage   MeSH
• Axitinib * therapeutic use   pharmacology   administration & dosage   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   pharmacology   administration & dosage   MeSH
• Carcinoma, Renal Cell * drug therapy   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Nivolumab * therapeutic use   pharmacology   administration & dosage   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Pyridines therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH
• Names of Substances
• Anilides * MeSH
• Axitinib * MeSH
• cabozantinib MeSH Browser
• Antibodies, Monoclonal, Humanized * MeSH
• Nivolumab * MeSH
• pembrolizumab MeSH Browser
• Pyridines MeSH

BACKGROUND: Pembrolizumab plus lenvatinib is a treatment option for metastatic Renal Cell Carcinoma (mRCC). In the ARON-1 study we investigated we the real-world experiences gained from the use of this combination for mRCC. METHODS: We retrospectively investigated real-world clinical outcomes of mRCC patients receiving pembrolizumab plus lenvatinib within the ARON-1 study. Overall survival (OS) was calculated from the start of pembrolizumab plus lenvatinib to death for any cause. Progression-Free Survival (PFS) was defined as the time from the start of pembrolizumab to progression or death from any cause. Duration of response (DoR) was defined as the time from the start of pembrolizumab to disease progression or death, whichever occurred first, in patients who achieved complete remission (CR) or partial response (PR). Overall Response Rate (ORR) was defined as the proportion of patients who achieve a CR or PR per RECIST criteria. Adverse events were retrospectively collected from electronic and paper charts and categorized by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: Overall, we included 202 mRCC patients treated with pembrolizumab plus lenvatinib. The median follow-up time was 15.1 months. The median OS was not reached (NR), with a median PFS of 25.6 months and an Overall Response Rate (ORR) of 59%. The median Duration of Response (DoR) was 26.2 months. G3-G4 adverse events (AEs) were observed in 92 patients (46%), with hypertension being the most common AE (13%). CONCLUSIONS: Pembrolizumab plus lenvatinib is an effective and tolerable treatment for mRCC also in the real-world setting.

• Keywords
• ARON- 1, Immune-combinations, Lenvatinib, Pembrolizumab, Real-world data, Renal cell carcinoma, Survival,
• MeSH
• Quinolines * therapeutic use   administration & dosage   pharmacology   MeSH
• Adult MeSH
• Phenylurea Compounds * therapeutic use   administration & dosage   pharmacology   MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   administration & dosage   pharmacology   MeSH
• Carcinoma, Renal Cell * drug therapy   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Quinolines * MeSH
• Phenylurea Compounds * MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• lenvatinib MeSH Browser
• pembrolizumab MeSH Browser

Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.

• Keywords
• lenvatinib, lenvatinib plus pembrolizumab, pembrolizumab, renal cell carcinoma,
• MeSH
• Quinolines * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Phenylurea Compounds * administration & dosage   therapeutic use   MeSH
• Antibodies, Monoclonal, Humanized * administration & dosage   therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   mortality   secondary   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged MeSH
• Sunitinib * administration & dosage   therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Names of Substances
• Quinolines * MeSH
• Phenylurea Compounds * MeSH
• Antibodies, Monoclonal, Humanized * MeSH
• lenvatinib MeSH Browser
• pembrolizumab MeSH Browser
• Sunitinib * MeSH

PURPOSE: CheckMate 914 is a two-part, randomized phase III trial evaluating adjuvant nivolumab plus ipilimumab (part A) or adjuvant nivolumab monotherapy (part B) versus placebo in mutually exclusive populations of patients with localized renal cell carcinoma (RCC) at high risk of postnephrectomy recurrence. Part A showed no disease-free survival (DFS) benefit for adjuvant nivolumab plus ipilimumab versus placebo. We report results from part B. METHODS: Patients were randomly assigned (2:1:1) to nivolumab (240 mg once every 2 weeks for up to 12 doses), placebo, or nivolumab (240 mg once every 2 weeks for up to 12 doses) plus ipilimumab (1 mg/kg once every 6 weeks for up to four doses). The planned treatment duration was 24 weeks (approximately 5.5 months). The primary end point was DFS per blinded independent central review (BICR) for nivolumab versus placebo; safety was a secondary end point. RESULTS: Overall, 825 patients were randomly assigned to nivolumab (n = 411), placebo (n = 208), or nivolumab plus ipilimumab (n = 206). With a median follow-up of 27.0 months (range, 18.0-42.4), the primary end point of improved DFS per BICR with nivolumab versus placebo was not met (hazard ratio [HR], 0.87 [95% CI, 0.62 to 1.21]; P = .40); the median DFS was not reached in either arm, and 18-month DFS rates were 78.4% versus 75.4%. The HR for DFS per investigator was 0.80 (95% CI, 0.58 to 1.12; P = .19). Grade 3-4 all-cause adverse events (AEs) occurred in 17.2%, 15.0%, and 28.9% of patients with nivolumab, placebo, and nivolumab plus ipilimumab, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6%, 1.0%, and 28.4%, respectively. CONCLUSION: Part B of CheckMate 914 did not meet the primary end point of improved DFS for nivolumab versus placebo in patients with localized RCC at high risk of postnephrectomy recurrence.

• MeSH
• Chemotherapy, Adjuvant MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Ipilimumab * therapeutic use   administration & dosage   adverse effects   MeSH
• Carcinoma, Renal Cell * drug therapy   surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * MeSH
• Kidney Neoplasms * drug therapy   pathology   surgery   MeSH
• Nephrectomy * MeSH
• Nivolumab * therapeutic use   administration & dosage   adverse effects   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Ipilimumab * MeSH
• Nivolumab * MeSH

INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria. MATERIALS AND METHODS: This retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 524 favorable-risk patients were included in the analysis. After a median follow-up of 37.2 months, the median OS in the overall population was 56.1 months. There was no significant difference in OS between patients receiving sunitinib and those receiving TKI + ICI combinations (p = 0.761). Patients on TKI + ICI had significantly longer PFS compared to patient treated with sunitinib (30.7 vs 22.9 months, p = 0.007). Analysis of OS and PFS based on metastatic site revealed that patients with bone metastases benefited more from ICI plus TKI (56 patients with bone metastases receiving IO + TKI, 38 received pembrolizumab plus axitinib, 15 cabozantinib plus nivolumab and 3 pembrolizumab plus lenvatinib), while sunitinib was more effective for pancreatic and glandular metastases. Additionally, the number of metastatic sites played a role, with TKI plus ICI showing superiority in patients with a single metastatic site. The time from RCC diagnosis to metastatic disease also impacted outcomes, with TKI plus ICI being more effective in patients with a shorter interval (i.e., < 36 months). CONCLUSIONS: The choice between upfront combination or monotherapy for metastatic favorable prognosis RCC remains a current issue. While combination therapy offers prolonged PFS, it does not necessarily translate to improve OS compared to sunitinib. This real-world study supports the superiority in terms of PFS of TKI plus ICI vs TKI monotherapy but not in OS. Probable, other clinical factors should be taking into account to make clinical treatment decisions in this setting.

• Keywords
• ARON-1 study, Good favorable-risk IMDC criteria, Immune-based combinations, Immunotherapy, Renal cell carcinoma,
• MeSH
• Quinolines therapeutic use   administration & dosage   MeSH
• Adult MeSH
• Phenylurea Compounds therapeutic use   administration & dosage   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   immunology   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   immunology   mortality   pathology   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Pyridines MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Sunitinib * therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH
• Names of Substances
• cabozantinib MeSH Browser
• Quinolines MeSH
• Phenylurea Compounds MeSH
• Immune Checkpoint Inhibitors * MeSH
• Protein Kinase Inhibitors MeSH
• lenvatinib MeSH Browser
• Pyridines MeSH
• Sunitinib * MeSH

BACKGROUND: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. OBJECTIVE: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. METHODS: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. RESULTS: In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. CONCLUSIONS: The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Adult MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   pathology   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

INTRODUCTION: Combined immuno-oncology (IO) regimens are the cornerstone of the current front-line systemic therapy for metastatic renal cell carcinoma (mRCC). Despite the fact that combined IO regimens show high efficacy, they are often accompanied by a wide spectrum of immune-related adverse effects (irAEs). CASE PRESENTATION: We describe a case of rare irAEs manifested as giant cell temporal arteritis (GCA) followed by severe encephalopathy occurring after continuing immunotherapy in a 66-year-old man with mRCC receiving a combination of ipilimumab and nivolumab in the first line of systemic therapy. GCA occurred 4 months after the initiation of IO and responded promptly to the low-dose prednisone therapy. Four months after the continuation of nivolumab maintenance, the patient was hospitalized due to severe irAE encephalopathy which presented as psycho-behavioral abnormalities and progressive cognitive decline. He was treated with high-dose methylprednisolone which led to complete resolution of the symptoms and IO was permanently discontinued. The patient achieved a durable partial response. CONCLUSION: Both GCA and the subsequent encephalopathy in our patient responded well to the corticosteroid therapy, leading to the complete resolution of the symptoms and the patient achieved a durable partial response. Although the risk of severe neurologic irAEs affecting the central nervous system induced by IO re-administration, following previous discontinuation due to irAE, is not well-defined because of their rarity, this case highlights the need for caution, particularly in cases with a history of previous irAE-associated GCA.

• Keywords
• Encephalopathy, Giant cell arteritis, Immune-related adverse effects, Immune-related adverse events, Immunotherapy, Nivolumab, Renal cell carcinoma,
• Publication type
• Journal Article MeSH
• Case Reports MeSH

PURPOSE: Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). METHODS: Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. RESULTS: Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. CONCLUSION: RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

• MeSH
• Adenocarcinoma * drug therapy   pathology   mortality   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Esophagogastric Junction * pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Esophageal Neoplasms * drug therapy   pathology   mortality   MeSH
• Stomach Neoplasms * drug therapy   pathology   mortality   MeSH
• Nivolumab * therapeutic use   administration & dosage   adverse effects   MeSH
• Lymphocyte Activation Gene 3 Protein * MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Lag3 protein, human MeSH Browser
• Nivolumab * MeSH
• Lymphocyte Activation Gene 3 Protein * MeSH

BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

• Keywords
• ARON-1 study, Gender differences, Immune-based combinations, Immunotherapy, NCT05287464, Renal cell carcinoma,
• MeSH
• Adult MeSH
• Immunotherapy methods   MeSH
• Immune Checkpoint Inhibitors therapeutic use   MeSH
• Carcinoma, Renal Cell * mortality   immunology   drug therapy   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Kidney Neoplasms * mortality   immunology   drug therapy   pathology   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sex Factors MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Names of Substances
• Immune Checkpoint Inhibitors MeSH

Renal cell carcinoma (RCC) is a common malignancy frequently diagnosed at the metastatic stage. We performed a comprehensive analysis of the tumor immune microenvironment (TIME) in RCC patients, including the peritumoral tissue microenvironment, to characterize the phenotypic patterns and functional characteristics of infiltrating immune cells. T cells from various compartments (peripheral blood, tumor, peritumoral area, and adjacent healthy renal tissue) were assessed using flow cytometry and Luminex analyses, both before and after T cell-specific stimulation, to evaluate activation status and migratory potential. Our findings demonstrated that tumor-infiltrating lymphocytes (TILs) exhibited heightened cytokine production compared to peritumoral T cells (pTILs), acting as the primary source of cytotoxic markers (IFN-γ, granzyme B, and FasL). CD8+ T cells primarily employed Fas Ligand for cytotoxicity, while CD4+ T cells relied on CD107a. In addition, a statistically significant negative correlation between patient mortality and the presence of CD4+CD107+ pTILs was demonstrated. The engagement with the PD-1/PD-L1 pathway was also more evident in CD4+ and CD8+ pTILs as opposed to TILs. PD-L1 expression in the non-leukocyte fraction of the tumor tissue was relatively lower than in their leukocytic counterparts and upon stimulation, peripheral blood T cells displayed much stronger responses to stimulation than TILs and pTILs. Our results suggest that tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells retain their capacity to respond to stimulatory signals.

• Keywords
• CAFs, CD8 T cells, Kidney cancer, PECAM-1, RCC TME, Renal carcinoma immunotherapy, Tumor immune microenvironment, Tumor-infiltrating lymphocytes, cytotoxicity, kidney cancer cytokines, peritumoral tissue,
• Publication type
• Journal Article MeSH