Immunology research update from www.immunopaedia.org.za.
In a recent paper published in Cancer Cell, researchers have identified patterns of immune cells within tumours that help with predicting if patients with renal/kidney cancer will respond to successfully to immunotherapy.
The most common type of kidney cancer, comprising 75% of cases, is clear cell renal cell carcinoma (ccRCC). Treatment of this form of cancer usually involves immunotherapy which is a form of drug treatment guiding immune cells into recognising and attacking cancer cells. However, this is not always effective and may not be successful, particularly for kidney cancers as there is no way to currently predict if it will be effective in an individual patient.
Au, et al., investigated 115 tumour samples from 15 people suffering from metastatic clear cell renal cell carcinoma, all of whom were receiving immunotherapy drug nivolumab as part of the ADAPTeR clinical trial. ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. In this study the authors presented an integrated analysis of response to nivolumab and whole-exome and RNA sequencing (RNA-seq), TCR profiling, and immunohistochemistry/multiple immunofluorescence (IHC/mIF); as well as high-dimensional flow cytometry across longitudinal, multiregion fresh tumor samples in this cohort (Figure 2). It was imperative for this study that multiple samples were taken from different parts of the kidney tumours as well as tumours that have spread to other organs as from each patient as this provided them with a comprehensive analysis of the effects of the drug and for metastatic profiling.
The study focused on harvesting tumour samples at various stages of cancer treatment i.e. before immunotherapy, nine weeks after treatment started, after surgery (at tumour removal), and if the treatment seized and stopped working. It must be noted that for three individuals, samples were collected after the patient had died (PEACE post-mortem research programme).
Au, et a., reviewed aimed to charactise the different tumours and measure the immune response to see any positive response to immunotherapy. They reported through genomic analyses show no correlation between tumour molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. In addition, the T cell receptor (TCR) analysis revealed a significantly higher number of expanded TCR clone’s pre-treatment in responders suggesting pre-existing immunity (Figure 3). Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. In short, they found that the increased number of specific T cell receptors (clones), proteins present in the tumour before treatment, correlated with an increased chance of positive immunotherapy response. In addition, if the T cell receptors numbers were maintained during treatment, this was a sufficient predictor that treatment would be effective. This is an important study as it elucidates why immunotherapy sometimes works and sometimes doesn’t.
In their own words:
“In conclusion, in this prospective study, we reveal features of anti-PD-1 response and resistance in ccRCC. We identified tumor-specific T cells with cytotoxic features in ccRCC, which hold promise for development of adoptive cellular therapy for this cancer…this dissection of immune changes under nivolumab provides the foundation for understanding response to combination therapies. Finally, our multi-omic analysis framework provides a template and highlights challenges for future immuno-oncology biomarker studies in ccRCC.” (Au, et al., 2021).
Journal Article: Au, et al., 2021. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer Cell.