SUO 2019: Employing Multiparametric Profiling to Characterize Immunotherapy Responders in Clear Cell Renal Cell Carcinoma

Washington, DC ( As part of the Research Scholars Update at SUO 2019, Dr. Brandon Manley discussed his work employing multiparametric profiling to characterize immunotherapy responders in clear cell renal cell carcinoma. Renal cell carcinoma represents a heterogeneous group of malignancies composed of diverse histologic and genetic assembly, and there are almost 64,000 new cases a year in the US. Over 30% of patients present with metastatic renal cell carcinoma, whereas those with advanced local disease (pT3 or pT4) have close to 50% recurrence rates at 5 years.

Within the last 18 months, combination therapies in advanced RCC have emerged, however, there is still a subset of patients that do not respond to therapy. Currently, Dr. Manley notes that there is no clear path forward. There are several preferred options, several recommended options, and then when patients fail it is essentially dealer’s choice as to what regimen is used. Dr. Manley’s work focused on characterizing in parallel the immunophenotype and mutational profiles found in locally advanced metastatic ccRCC as they correspond with the patient’s response to immunotherapy and clinical outcomes. His group’s hypothesis is that response to systemic therapy (immunotherapy and/or targeted therapy) can be predicted by using integrated mutational profiling with immunophenotypes in locally advanced and metastatic ccRCC. Ultimately, the goal is to determine candidate markers/combinations for future studies and development.

Dr. Manley’s team assessed 58 samples from 51 patients, all with metastatic RCC and treated with either immunotherapy or TKIs. There were two panels evaluated, including CD3, CD8, FOXP3, and TBET (Panel 1) and CD68, CD163, CD206 and PDL1 (Panel 2). Samples were multiplexed immunoflores cence, followed by HALO digital quantitative tissue analysis, and finally biostatistical analysis. These patients had a mutation profile comparable to typical clear cell RCC patients, including VHL, PDRM1, BAP1, SETD2 and TP53. There were significant differences for CD68 cells across regions of interest in both primary and metastatic tumor samples. CD68+ cells were enriched in tumor and interface compared to stroma in clear cell RCC in both primary and metastatic samples. There were statistically significant increases in macrophage M2 polarized markers in metastatic samples (CD68+, CD163+, CD206+) across most regions of interest.

On survival analysis, decreased CD68 in the tumor region of interest, the interface, and stroma were all associated with increased overall survival. Second, increased CD3+ Tbet+ was associated with longer survival after immunotherapy across all regions. Third, there was no association with CD8+ for any outcomes.

Dr. Manley concluded with several take-home messages:

  • CD68+ staining was significantly correlated with longer survival including after immunotherapy across the tumor microenvironment after controlling for relevant clinical variables in primary ccRCC tumors
  • High number of Tbet+ TILS was associated with a favorable survival after immunotherapy – the hallmark of Th1 transcription factor that controls the expression of IFN-gamma
  • M2 polarization (CD163+/CD206+) and Tbet+ was enriched among metastatic tumors compared to the primary lesions.
  • Changes in the clinical relevant tumor microenvironment with metastatic tumor samples included lymphoid (CD68) 🡪 myeloid (FOXP3)
  • There was no statistically significant tumor heterogeneity in immune profiles among matched pairs but there was a trend for PD-L1
  • CD8+ had no clinical associations in this cohort

Presented by: Brandon Manley, MD, Moffitt Cancer Center, Tampa, Florida

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md, at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC