Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study)

<b>Introduction:</b> The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as <i>responders</i> (progression-free survival ≥ 12 months) and <i>non-responders</i> (progression-free survival &lt; 3 months). <b>Areas covered:</b> The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. <i>Responders</i>‘ tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (<i>p</i> = 0.014), higher CD56 expression (<i>p</i> = 0.046) and higher CD8/CD4 ratio (<i>p</i> = 0.030). <b>Expert opinion/commentary:</b> The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy. There is a critical lack of predictive biomarkers for patients with metastatic renal cell carcinoma receiving immunotherapy, therefore the identification of patients likely to benefit from this treatment represents a pressing clinical challenge. The Meet-URO 18 study is a multicentric, retrospective, translational study that delves into the immune tumor microenvironment (I-TME) of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line or beyond. Patients were categorized as <i>responders</i> (progression-free survival ≥ 12 months) and <i>non-responders</i> (progression-free survival &lt; 3 months). Digital multitarget immunohistochemical analyses were performed on the I-TME of tumor samples of primary tumors or metastases. Primary analyses revealed that <i>responders</i> exhibited lower CD4 expression and higher levels of phosphorylated mTOR and CD56. Further extensive analysis of the I-TME focused on T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression assessed on tumor cells, and PD-L1 expression (SP263) assessed on both tumor and immune cells. <i>Responders</i> tumor tissue showed significantly lower CD4 expression, higher CD56 expression and a higher CD8/CD4 ratio compared with <i>non-responders</i>. Other parameters, including PD-L1 expression, did not reach statistical significance. This secondary analysis highlights the emerging significance of CD56 as a putative biomarker for immunotherapy, suggesting a critical role for regulatory CD4⁺ cells over cytotoxic CD8⁺ cells.