The Future of Perioperative Therapy in Advanced Renal Cell Carcinoma: How Can We Prosper?

Patel, Hiten D.; Puligandla, Mäneka; Shuch, Brian; Leibovich, Bradley C.; Kapoor, Anil; Master, Viraj A.; Drake, Charles G.; Heng, Daniel Yick Chin; Lara, Primo N.; Choueiri, Toni K.; Maskens, Deborah; Singer, Eric A.; Eggener, Scott E.; Svatek, Robert S.; Stadler, Walter M.; Cole, Suzanne; Signoretti, Sabina; Gupta, Rajan T.; Michaelson, M. Dror; McDermott, David F.; Cella, David; Wagner, Lynne I.; Haas, Naomi B.; Carducci, Michael A.; Harshman, Lauren C.; Allaf, Mohamad E.

doi:10.2217/fon-2018-0951

Cited by 38 publications

(25 citation statements)

References 34 publications

(45 reference statements)

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“…Cytotoxic CD8 + T cells are key effectors of the adaptive anti-tumor immune response (7) and the abundance of CD8 + T cells in solid cancers is generally associated with better survival in cancer patients (8)(9)(10). However, in RCC, tumor-infiltrating lymphocyte (TIL) abundance is inversely correlated with survival (11)(12)(13). Biomarker analysis from recent clinical trials comparing PD-1 blockade versus anti-angiogenic inhibitors and combination therapies in treatment-naïve ccRCC patients also demonstrated the inverse relationship between T cell infiltration and clinical outcomes (14,15).…”

Section: Introductionmentioning

confidence: 99%

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Vishwakarma

Borcherding

Chimenti

et al. 2019

Preprint

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One Sentence Summary: Single-cell RNA-sequencing reveals unique lymphoid and myeloid gene programs with putative functions in clear cell renal cancer patients Abstract: The immune cells within the tumor microenvironment are considered key determinants of response to cancer immunotherapy. Immune checkpoint blockade (ICB) has transformed the treatment of clear cell renal cell carcinoma (ccRCC), although the role of specific immune cell states remains unclear. To characterize the tumor microenvironment (TME) of ccRCC, we applied single-cell RNA sequencing (scRNA-seq) along with paired T cell receptor sequencing to map the transcriptomic heterogeneity of 24,904 individual CD45 + lymphoid and myeloid cells in matched tumor and blood from patients with ccRCC. We identified multiple distinct immune cell phenotypes for B and T (CD4 and CD8) lymphocytes, natural kill (NK) cells, and myeloid cells. Evaluation of T cell receptor (TCR) sequences revealed limited shared clonotypes between patients, whereas tumor-infiltrating T cell clonotypes were frequently found in peripheral blood, albeit in lower abundance. We further show that the circulating CD4 + T cell clonality is far less diverse than peripheral CD8 + . Evaluation of myeloid subsets revealed unique gene programs defining monocytes, dendritic cells and tumor-associated macrophages. In summary, here we have leveraged scRNA-seq to refine our understanding of the relative abundance, diversity and complexity of the immune landscape of ccRCC. This report represents the first characterization of ccRCC immune landscape using scRNA-seq. With further characterization and functional validation, these findings may identify novel sub-populations of immune cells amenable to therapeutic intervention. [Main Text:]

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Section: Introductionmentioning

confidence: 99%

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Vishwakarma

Borcherding

Chimenti

et al. 2019

Preprint

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“…Cytotoxic tumor-infiltrating lymphocytes (TILs), in particular CD8 + T cells are key effectors of the adaptive antitumor immune response 7 and abundance of CD8 + T cells in solid cancers is generally associated with better survival in cancer patients [8][9][10][11] . However, in ccRCC, immune cell abundance is inversely correlated with survival, specifically TILs including CD8 + T cells [12][13][14][15] . Biomarker analysis results from recent clinical trials also supported the negative prognostic significance of T-cell infiltrates in the absence of immunotherapy within treatment-naive ccRCC patients 16,17 .…”

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confidence: 99%

Mapping the immune environment in clear cell renal carcinoma by single-cell genomics

et al. 2021

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Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45+ lymphoid and myeloid cells in matched tumor and blood from three patients with ccRCC. We also included 11,367 immune cells from four other individuals derived from the kidney and peripheral blood to facilitate the identification and assessment of ccRCC-specific differences. There is an overall increase in CD8+ T-cell and macrophage populations in tumor-infiltrated immune cells compared to normal renal tissue. We further demonstrate the divergent cell transcriptional states for tumor-infiltrating CD8+ T cells and identify a MKI67 + proliferative subpopulation being a potential culprit for the progression of ccRCC. Using the SCRS gene expression, we found preferential prediction of clinical outcomes and pathological diseases by subcluster assignment. With further characterization and functional validation, our findings may reveal certain subpopulations of immune cells amenable to therapeutic intervention.

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“…Cancer staging that accurately reflects patient outcomes not only provides patients with key prognostic information but also guides the construction of postoperative surveillance schedules and the selection of patients for systemic therapy and enrollment in clinical trials 4,11 . Specifically, the current study assessed the survival of patients with LN+ stage III kidney cancer compared with their counterparts with stage III disease without LN involvement.…”

Section: Discussionmentioning

confidence: 99%

Impact of pathologic lymph node‐positive renal cell carcinoma on survival in patients without metastasis: Evidence in support of expanding the definition of stage IV kidney cancer

Srivastava

Rivera‐Núñez

Kim

et al. 2020

Cancer

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Background Stage III renal cell carcinoma (RCC) encompasses both lymph node‐positive (pT1‐3N1M0) and lymph node–negative (pT3N0M0) disease. However, prior institutional studies have indicated that among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease. The objective of the current study was to validate these findings using a large, nationally representative sample of patients with kidney cancer. Methods Patients with AJCC stage III or stage IV RCC were identified using the National Cancer Data Base (NCDB). Patients were categorized as having lymph node‐positive stage III (pT1‐3N1M0), lymph node–negative stage III (pT3N0M0), or stage IV metastatic (pT1‐3 N0M1) disease. Cox proportional hazards models compared outcomes while adjusting for comorbidities. Kaplan‐Meier estimates illustrated relative survival when comparing staging groups. Results A total of 8988 patients met the inclusion criteria, with 6587 patients classified as having lymph node–negative stage III disease, 2218 as having lymph node‐positive stage III disease, and 183 as having stage IV disease. Superior survival was noted among patients with lymph node–negative stage III disease, but similar survival was noted between patients with lymph node‐positive stage III and stage IV RCC, with 5‐year survival rates of 61.9% (95% confidence interval [95% CI], 60.3%‐63.4%), 22.7% (95% CI, 20.6%‐24.9%), and 15.6% (95% CI, 11.1%‐23.8%), respectively. Conclusions Current RCC staging systems group pT1‐3N1M0 and pT3N0M0 disease as stage III disease. However, the results of the current validation study suggest the need for further stratification and even placement of patients with pT1‐3N1M0 disease into the stage IV category. Staging that accurately reflects oncologic prognosis may help clinicians better counsel and select patients who might derive the most benefit from lymphadenectomy, adjuvant systemic therapy, more rigorous imaging surveillance, and clinical trial participation.

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The Future of Perioperative Therapy in Advanced Renal Cell Carcinoma: How Can We Prosper?

Cited by 38 publications

References 34 publications

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

Mapping the immune environment in clear cell renal carcinoma by single-cell genomics

Impact of pathologic lymph node‐positive renal cell carcinoma on survival in patients without metastasis: Evidence in support of expanding the definition of stage IV kidney cancer

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