T-cell infiltration and differential gene expression were found to be associated with response to nivolumab treatment among patients with advanced clear cell renal cell carcinoma (RCC), according to the results of a study published in the Journal of ImmnoTherapy of Cancer.

Programmed death-ligand 1 (PD-L1) expression and tumor mutational burden do not predict response to immunotherapy in RCC. “To address this gap, we report here the first molecular characterization of nivolumab response,” the authors wrote.

The study analyzed data from 69 patients who participated in the phase 1b CheckMate 009 trial, in which patients with advanced clear cell RCC underwent treatment with nivolumab. Baseline and day-28 biopsy specimens were evaluated for lymphocyte infiltration, PD-L1 expression, T-cell clonality, and differences in gene expression.

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There were 311 genes differentially expressed at baseline, with increased expression of immune response in silico (IRIS) immune-cell transcripts that included lineages of myeloid and lymphoid cells. The authors noted that this is “suggesting a pre-existing immunologically active tumor environment in responders.”

At 28 days after treatment initiation, there were 779 genes differentially expressed, again with increased expression of IRIS immune-cell transcripts among responders.

Within responders, the authors noted that decreased gene expression included the EGFR and Wnt-pathway members, with the greatest decrease in MMP3. “The decrease in therapy suggests that the MMP3 transcript originates in tumor or tumor-specific stromal cells,” the authors wrote.

T-cell infiltration at baseline (P =.03) and at day 28 (P <.01) was also significantly associated with response to nivolumab. However, some nonresponders also had high levels of T-cell infiltration but with activation of the RIG-I-MDA5 pathway.

T-cell receptor clonality was not associated with response.

The authors concluded that “we have shed light on two phenomena related to primary resistance to checkpoint inhibitors: low T-cell infiltrate at baseline and high T-cell infiltrate on therapy in the absence of response.”


Ross-Macdonald P, Walsh AM, Chasalow SD, et al. Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. J Immunother Cancer. 2021;9(3):e001506. doi:10.1136/jitc-2020-001506