Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Abstract

TGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.

Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treat low-burden metastases

“…In contrast, NK cell transfer did not alter the proportion of exhausted or PEX CD8 + T cells (Figure 5D and Figure 5-figure supplement 1A). The expression of PD-1, Lag3, Tim3, CD44, CD62L, Ly108 and GrzB by SCL, exhausted, and PEX CD8 + T cells in our analysis is consistent with the known characteristics of these cell populations (Figure 5-figure supplement 1B) (Andreatta et al, 2021; Castiglioni et al, 2023; Martinez-Usatorre et al, 2020). Thus, overall, transfer of the IL-15/IL-12-conditioned syngeneic NK cells augmented the activation of cDC1s and cDC2s, as well as the levels and activation of Foxp3 - CD4 + T cells, naïve CD8 + T cells and SCL CD8 + T cells in metastatic lungs.…”

“…These results indicate that IL-10 of transferred NK cells inhibits activation of naïve CD8 + T cells, whereas IFN-γ of transferred NK cells promotes their effector differentiation and proliferation. We further examined stem cell-like (SCL) CD8 + T cells that are Tim3 - in PD-1 lo Lag3 - CD8 + cells (Figure 5-figure supplement 1A) (Castiglioni et al, 2023), and detected an increase of total and Ki67 + SCL CD8 + T cells in mice that received WT or Il10 -/- , but not Ifng -/- , NK cells (Figure 5D). Transfer of Il10 -/- NK cells resulted in a higher level of SCL CD8 + T cells than when WT NK cells were transferred (Figure 5D).…”

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

“…Interestingly, microtubule inhibitors like colchicine can improve the cytotoxic efficiency of CTLs in collagen-rich environments [ 91 ]. Notably, the use of TGF-β blockade antibodies in combination with anti-PD-L1 antibodies reduces TGF-β signaling in stromal cells, thereby enhancing T cell infiltration and triggering potent anti-tumor immune responses [ 92 ].…”

CD8+ T cell-based cancer immunotherapy

“…However, to change the fate of being eliminated, some tumor cells obviate such mechanism and deliver signal stimulation to immune cells, triggering T cell dysfunction and apoptosis [ 52 ]. Immunotherapy-based treatments, including immune checkpoint inhibitors (ICIs) typified by anti-PD-1/PD-L1 drugs, can re-activate immune cells by blocking immune checkpoints in cancer patients, so CD8 + T cytotoxicity against tumor cells can be restored [ 90 ].…”

“…Despite groundbreaking success of ICIs, their overall response rates (ORRs) in patients remain low for most cancer types. Differences in ICI responses among individuals may come from various interplays between aberrant tumors and changing immune cells, where significant increases in immune cell populations, such as CD8 + T cells, after ICI treatment can be commonly observed [ 90 , 96 ]. Accordingly, two major therapeutic strategies are proposed to improve the therapeutic responses in the clinical settings.…”