Cancer Cell: Determinants of anti-PD-1 response and drug resistance in advanced renal cell carcinoma

Renal clear cell carcinoma (ccRCC) is the most common type of kidney cancer, accounting for 70%-80% of kidney cancers, and the incidence is increasing worldwide
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ccRCC is one of the most severe types of solid tumors with immune infiltration.

Recently, the British Francis Crick Institute, University of London's Institute of Cancer Institute research team jointly published a report entitled on the Cell Cancer: Determinants of the Response Anti-PD-1 resistance in the Clear the Cell and the Cell renal carcinoma research papers
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ADAPTeR (NCT02446860) is a phase II single-arm open-label study of Nivolumab in the treatment of patients with metastatic ccRCC.
The patient’s primary and/or metastatic sites were multi-regional at baseline, at the 9th week, at the time of surgery, and when the disease progressed.
Tumor sampling
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The main purpose of ADAPTeR is to evaluate the molecular and tumor immune microenvironment (TME) characteristics throughout the treatment process

Through the ADAPTeR cohort, the research team found that the number of amplified TCR clones in Nivolumab responders before treatment increased significantly, maintaining a highly similar TCR cluster after treatment predicts the response, and Nivolumab-bound CD8+ T cells were amplified and expressed GZMK/B , Indicating that Nivolumab promotes the maintenance and replacement of previously expanded T cell clones, but only maintenance is related to the response, so maintaining and enhancing the pre-existing response is a key factor in the anti-PD-1 mode of action
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First, the research team performed whole exome and RNA sequencing (RNA-seq)
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They found that there are 10 human endogenous retrovirus (HERV) genes and 12 long terminal repeat (LTR) elements that distinguish responders from non-responders

Further analysis showed that compared with non-responders, tumors from responders had significantly higher levels of T cells before and after treatment, and the expression of CD3E, CD8A, GZMB, and TCF7 were also higher

At any point in time, the research team observed no difference in the number of T cells or the total expression of PD-1 among the responders
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The GZMB expression levels of responders and non-responders before treatment were lower

The question of whether tumor-specific T cells activated by immune checkpoint inhibitors are present in the tumor or whether they are replaced by new T cell clones recruited by TME is still under debate
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The research team sequenced the β-chain TCR sequences of 14 patients before and after treatment, including 64 tumors and 29 peripheral blood mononuclear cell (PBMC) samples

In summary, the study revealed the characteristics of ccRCC's anti-PD-1 response and drug resistance, and identified tumor-specific T cells with cytotoxic characteristics, which brought hope to the development of adoptive cell therapy for this cancer.

Original source:

Lewis Au, et al.