Cell blockbuster: discovering new targets for cancer vaccines

Cancerous cells produce mutant proteins that are not seen in healthy cells
.
These cancerous proteins, also called neoantigens, can alert the body's immune system

Neoantigens can drive effective anti-tumor T cell responses
.
In the past ten years, scientists have been exploring ways to help fight cancer through vaccination.

On September 16, 2021, the MIT research team published a research paper titled: Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors in the top international academic journal Cell
.

The study found that vaccination against certain tumor neoantigens can enhance the overall T cell response and help shrink tumors in mice.
This study helps determine which proteins should be included in cancer vaccines, targeting the proteins found in the study Vaccination can help awaken the dormant T cell population that targets these proteins, thereby strengthening the overall immune response
.

The research team previously constructed a KRAS/p53-driven (KP) orthotopic lung adenocarcinoma mouse model to express tumor-specific neoantigens
.
CD8 T cell neoantigens from both SIIN and SIY models are expressed in tumor cells in the form of fusion with luciferase, also known as LucOS

First, the research team performed longitudinal characterization of SIIN- and SIY-specific CD8 T cells in lung tumors of KP-LucOS mice
.
At the peak of the reaction, compared with SIY, SIIN can significantly promote the expansion of CD8 T cells

In order to further study the phenotypic differences between SIIN- and SIY-specific CD8 T cells, the research team performed single-cell RNA sequencing (scRNA-seq) and paired T cell receptor (TCR) sequencing at the peak of the reaction
.
The results showed that SIIN-specific cells were enriched due to the characteristics of "effector" and "depleted" T cells, while SIY-specific cells were enriched due to the lowly differentiated "naive" and "memory precursor" states (with TCF1+ progenitor cells).

The research team found that antigen dominance levels can be formed in tumors, which will significantly affect the phenotype of cells that respond to subdominant antigens
.
Competition with SIIN promotes the phenotype of TCF1+ progenitor cells between SIY-specific cells and hinders the differentiation to effector cell and depleted cell states

When the research team vaccinated mice with lung tumors with SIIN or SIY, they found that the tumors shrank by an average of 27%
.
After vaccination, CD8 T cell proliferation and cytotoxicity increased, continuing to refuel the reaction, while the CCR6+ population was significantly suppressed, thus achieving long-term tumor control effect, indicating that attempts to identify these suppressed reactions and specifically target them may be possible It will improve the patient's response to vaccine therapy

Overall, this work found a previously undescribed progenitor cell subpopulation, which is a subdominant group of antigens associated with impaired function and adverse reactions to immune checkpoint blockade
.
Vaccination eliminates this subpopulation and greatly enhances the ability of T cell populations to attack tumors, highlighting a strategy for optimally performing subneoantigen responses against tumors

Original source:

Megan L.
Burger, et al.
Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors .
Cell, 2021.