Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used data sets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients in order to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of non-silent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or beta2M revealed that an A-neohi/HLA-Ahi or ABC-neohi/beta2M hi phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules (CD8A, perforin (PRF1) and granzyme A (GZMA)), however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PD-L2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high priority targets for modulating immune responses in ccRCC patients. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity.
- Received September 9, 2015.
- Revision received December 28, 2015.
- Accepted February 5, 2016.
- Copyright ©2016, American Association for Cancer Research.