Targeting non-canonical antigens unlocks functional T-cell responses in renal cell carcinoma
Jiahao Wang, Yihao Zhu, Xinyu He, Shenyi Yin, Yang He, Pengju Yao, Juan Li, Xuwen Li, Peiting Shi, Renzhi Qian, Zhiqing Xiao, Xiongjun Ye, Jianzhong Jeff Xi, Buqing YeBackground
Renal cell carcinoma (RCC) frequently exhibits favorable responses to immunotherapy, despite a low tumor mutational burden, suggesting a critical role for non-mutational antigens presented by human leukocyte antigen class I in activating CD8 + T cells.
Methods
To systematically identify non-canonical tumor-specific antigens, we developed an integrated proteogenomic approach to RCC samples by combining immunopeptidomics with exome and transcriptome sequencing. We subsequently primed and expanded antigen-reactive T cells in vitro, isolated a panel of antigen-specific T-cell receptors, and characterized their functionality. Finally, we investigated the tumor-killing and regression of non-canonical antigen-reactive T cells using patient-derived tumor-like cell clusters and mouse models.
Results
We discovered a diverse repertoire of non-canonical tumor-specific antigens derived from human endogenous retroviruses (hERVs) and long non-coding RNAs (lncRNAs), many of which were shared across patients. Single-cell RNA sequencing further revealed that T cells reactive to these antigens were enriched within exhausted subsets in the tumor microenvironment, indicative of persistent antigen-specific stimulation. Functionally, T cells engineered to recognize these non-canonical antigens mediated potent tumor cell killing both in vitro and in vivo. Our findings establish hERV-derived and lncRNA-derived antigens as key drivers of RCC immunogenicity and highlight their strong potential as targets for T-cell-based immunotherapy.
Conclusions
Our work is the first to demonstrate that non-canonical antigens drive immunogenicity in low-mutation RCC, thereby resolving a key question in cancer immunology—how tumors with low mutational burden can provoke robust T-cell responses.