Immunohistochemical (IHC) analyses of the immune tumor microenvironment (I-TME) in metastatic renal cell carcinoma (mRCC) patients (pts) receiving immunotherapy: secondary analyses of the Meet-URO 18 study

Background: Prognostic and/or predictive biomarkers of mRCC treated with immune checkpoint inhibitors are lacking and their identification to select pts most likely to benefit from immunotherapy is still an unmet clinical need. The Meet-URO 18 study is a translational multicenter study assessing the I-TME in mRCC pts receiving ⩾2nd line nivolumab divided according to clinical benefit in responders vs non-responders (progression-free survival ⩾12 vs ⩽3 months, respectively). The primary analyses showed the correlation of responders with lower CD4 expression and higher levels of phosphorylated mTOR (ph-mTOR) and CD56; moreover, non-responders were associated with a higher percentage of clear cell histology and grading. An extended analysis focused on the I-TME was then conducted. Methods: Digital multitarget IHC analyses were performed on the I-TME of the primary tumor or the metastases assessing T-lineage (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68) and granulocytes (CD15). Ph-mTOR and CD56 on tumor cells were also analysed. PD-L1 (SP263) expression assessment on both tumor and immune cells was included. The biomarkers’ expression was estimated as median and interquartile range (IQR). Differences between the two pts groups were considered statistically significant with a p value of < 0.05. Results: Overall, 161 tumor tissue samples (57.1% primary tumors, 42.9% metastases) were evaluated. Responders’ tumor samples (N = 90, 55.9%) presented significantly lower CD4 expression [median (IQR): 30 (14-60) vs 60 (20-80), p = 0.014] and higher CD56 expression [median (IQR): 10 (0-90) vs 0 (0-15), p = 0.046] and CD8/CD4 ratio [median (IQR): 1.5 (0.67-2.70) vs 1 (0.31- 2.10), p = 0.030] compared to non-responders’ tumor samples (N = 71, 44.1%). All other parameters, including PD-L1 expression, did not reach statistical significance. Conclusions: Cancers that benefit from nivolumab are characterized by low CD4 expression and high CD56 expression and CD8/CD4 ratio. This secondary analysis highlights again the relevance of CD56 as an emerging biomarker of immunotherapy benefit and the more influencing role of the regulatory CD4+ cells than the cytotoxic CD8+ cells. Further gene signature analyses are ongoing to integrate IHC analyses.