Characterization of Tumor and Immune Tumor Microenvironment of Primary Tumors and Metastatic Sites in Advanced Renal Cell Carcinoma Patients Based on Response to Nivolumab Immunotherapy: Preliminary Results from the Meet-URO 18 Study

SIMPLE SUMMARY: The identification of clinical and tumor factors to identify patients who most benefit from oncological treatments is a crucial clinical unmet need. We studied differences in the tumor microenvironment assessed using an easy method called immunohistochemistry between cancers in patients who did or did not respond to an immunotherapy called nivolumab. The tumors in those patients who most benefitted from nivolumab were characterized by the following: a poor presence of specific immune cells (CD4+), which are likely to have an immunosuppressive role; a high expression of the CD56 marker on tumor cells, which plays a role in cell cytotoxicity; and a high expression of the phosphorylated form of the mTOR protein in tumor cells, which regulates the function of intra-tumor inflammatory cells and cancer cells. Further immunohistochemical and genomic analyses are planned to deeply examine the prognostic role of the tumor microenvironment. ABSTRACT: Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed. Results: A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression (p = 0.059) and CD8+/CD4+ ratio (p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading. Conclusions: Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned.