The establishment and maintenance of anti-tumor immune responses are the objectives of cancer immunotherapy. Despite recent promising advances, the effectiveness of these approaches has been limited by the multiple immunosuppressive mechanisms developed by tumors (checkpoint). The aim of the present study was to demonstrate intratumor heterogeneity at the levels of immune escape strategies and tumor-host relationships. We focused on well-known checkpoints such as PD1/PDL1 and on a new checkpoint involving HLA-G and its receptors ILT2/ILT4. A prospective study was performed on 19 renal-cell carcinoma patients that were included during hospitalization for surgical tumor resection. Different areas of the tumor were collected for each patient and subjected to both immunohistochemical and flow cytometry analysis. Immune cells from peripheral blood were concomitantly analyzed for each patient. Our results show the heterogeneous expression of PD1/PDL1 and HLA-G/ILT in the various areas of the same tumor. Intratumor heterogeneity was found both at tumor cell and infiltrating immune cell levels. From a clinical point of view, this work highlights the functional redundancies of checkpoints and the need to adapt personalized poly-immunotherapy.