Broad immunomodulating effect of first-line Pazopanib in metastatic renal cell carcinoma patients

Abstract

Background: The impact of tyrosine kinase inhibitors (TKIs) on tumor immunity of patients (pts) with metastatic renal cell carcinoma (mRCC) is largely unknown. We investigated the activity of pazopanib in counteracting tumor-induced immunosuppression and boosting adaptive immune response. Methods: Sixteen mRCC pts receiving first-line Pazopanib were prospectively analyzed at baseline, 3 and 6 months for blood Immune profiling by multicolor cytofluorimetry. Gene expression analysis was performed by Illumina HT12v4 BeadChip Arrays. Data were evaluated by t-test, enrichment analysis and deconvolution algorithms. Results: Pazopanib administration (800 mg per os/daily) was associated with a significant decrease of cell subsets involved in immunosuppression, including CD14+ monocytes, monocytic CD14+ HLA-DRneg myeloid derived suppressor cells (MDSC) and CD14+PDL-1+ cells. Similarly, low density CD15+ granulocytic MDSC and CD4+ CD25high Foxp3+ regulatory T cells were reduced by treatment. Concomitantly, a boost of antitumor effectors, such as activated T lymphocytes (identified as CD3+PD-1dim T cells) and cytotoxic CD3-CD16+CD56dim NK cells, was observed. Changes were more evident at 3 months and in pts achieving clinical benefit (69%), defined as the sum of partial response and stable disease at first restaging. Interestingly, a statistically significant increase of lymphocyte/monocyte ratio, as determined by routine blood test was also detected. Gene expression analysis confirmed the immunoregulatory effects of pazopanib. By comparing with those collected after 3 months after treatment start and pre-treatment samples, pathway-enrichment analysis revealed a coherent modulation of NK Granzyme A, IL8 signaling and other immune-related pathways. Similarly, using deconvolution algorithms, we observed an enrichment of NK and CD8+ T cell transcripts. Conclusions: Pazopanib reshapes tumor immunity by reducing immunosuppressive cells (MDSC and Treg) and triggering T cells and NK effectors. These data provide a strong rationale for using Pazopanib both before an immunocheckpoints inhibitors and also in combination strategies based on the synergism between TKIs and immunotherapy.