Antigen Dominance Hierarchies Shape TCF1+ Progenitor CD8 T Cell Phenotypes in Tumors

Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes

“…Our findings also help to explain the diminished response to checkpoint blockade therapy during tumor progression recently reported in the KP model of lung adenocarcinoma (Burger et al, 2021). This work demonstrated that while tumor-specific CD8 + T cells initially numerically increased after checkpoint blockade, this boost did not occur 12 weeks after initiation (Burger et al, 2021).…”

“…Our findings also help to explain the diminished response to checkpoint blockade therapy during tumor progression recently reported in the KP model of lung adenocarcinoma (Burger et al, 2021). This work demonstrated that while tumor-specific CD8 + T cells initially numerically increased after checkpoint blockade, this boost did not occur 12 weeks after initiation (Burger et al, 2021). Given the role cDC1s play in regulating the response to checkpoint blockade, our data demonstrating a substantial reduction in migratory cDC1 in the dLN is consistent with the diminished checkpoint response seen at later time points in the KP model.…”

Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models

“…We obtained similar results in a KPO model. Collectively, these findings support the notion that progressing KP tumors harbor suppressed CD8 + T cells (44)(45)(46)52), which cannot be rescued by endogenously or exogenously expressing potential neoantigens. Published work indicated that KP tumor progression was accompanied by a phenotype switch in T regs , which up-regulated the expression of several activation markers and effector molecules (46).…”

“…We found that KP tumors highly express T reg cytokines including Ccl17, a T reg chemoattractant (49,50), and transforming growth factor- (Tgfb1), a pivotal T reg differentiation factor (fig. S6A) (51); accordingly, T regs were previously found to have immunosuppressive capacity in KP lung tumor models (44)(45)(46)52). Flow cytometry analysis of KP and KPM tumors indicated that a larger proportion of T regs expressed surface PD-1 compared to CD8 + or CD4 + FoxP3 − T cells, at both 1-and 4-week time points of analysis and independent of treatment: On average, the frequency of PD-1 + cells was two-to threefold higher in T regs than other T cell subsets (Fig.…”

“…Relatively abundant T regs and scant or dysfunctional effector CD8 + T cells characterize progressing KP tumors (44)(45)(46)52). Macrophages physically associate with T reg in KP tumors, and their elimination with a combination of a CSF1R antibody and cisplatin exhaustively depleted T regs from the tumor microenvironment.…”