A study published in the PNAS uncovered a subtype of T cells with robust tumor-killing capabilities that resist exhaustion, elucidating the cellular and molecular mechanisms behind their identification and activation. This study was conducted by the research team led by Dr. WANG Ying and Dr. SHI Yufang from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences.  

CD8⁺ T cells play a pivotal role in anti-tumor immune responses. Current tumor immunotherapy strategies based on CD8⁺ T cells, such as CAR-T and TCR-T cells, are burgeoning. However, their limited universality, inability of infiltration into solid tumors, susceptibility to exhaustion, and high production costs pose key challenges to tumor immunotherapy. One of the core issues is the lack of a universally effective prototype of T cells with broad tumor-killing abilities, necessary for developing “off-the-shelf” T cell therapy products.  

In this study, the researchers revealed that major histocompatibility complex (MHC) Ib-restricted CD8⁺ T (Ib-CD8⁺ T) cells possess broad-spectrum tumor-killing capabilities. This group of Ib-CD8⁺ T cells not only efficiently kills various tumor cells such as melanoma, colorectal cancer, lung cancer, and liver cancer, but can also directly eliminate tumor cells lacking MHC class I molecules, effectively targeting tumors without harming normal tissues.  

Through combined analysis using single-cell mRNA/TCR sequencing, the researchers identified that these tumor-killing Ib-CD8⁺ T cells expressed high levels of cytotoxic factors like IFNγ, GZMA, and GZMB, while showing low expression of exhaustion-related molecules like PD-1, TIM3, and TOX-1. When used in treating solid tumors, Ib-CD8⁺ T cells exhibited significant infiltration at the tumor site and oligoclonal expansion, effectively suppressing tumor growth and prolonging the lifespan of tumor-bearing mice. Similar tumor-killing CD8⁺ T cells were observed in human solid tumor tissues.  

Furthermore, the researchers elucidated the molecular basis for the activation and execution of the anti-tumor immune response by Ib-CD8⁺ T cells. They revealed that MHC class Ia molecules (MHC Ia) provided crucial signals for the activation and functional execution of Ib-CD8+ T cells, significantly reducing the activation threshold when they acted upon Ib-CD8⁺ T cells. Using gene editing techniques or neutralizing antibodies, they confirmed that the Tbet and NKG2D signaling pathways were critical for the pre-activation of Ib-CD8⁺ T cells' anti-tumor immune function by MHC Ia.  

The findings of this study not only expand the understanding of CD8⁺ T cell anti-tumor immune responses but also lay a solid foundation for developing tumor immunotherapy based on Ib-CD8⁺ T cells.