Abstract
The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.
Highlights
The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-programmed death 1 (PD-1)/PD-L1 therapy
Antitumor effect of anti-PD-L1 therapy was assessed in four syngeneic mouse tumor models: MC38 colon adenocarcinoma, B16 melanoma, and two triple-negative mammary cancers: AT-3 derived from the PyMT-MMTV model on an H-2b background and 4T1 on an H-2d background
Immunohistochemistry (IHC) analysis revealed sparse CD8+ T cells but abundant CD163+ tumorassociated macrophages (TAMs) in AT-3, B16, and 4T1 tumors compared to MC38 tumors (Supplementary Fig. 1b), consistent with a positive correlation between CD8+ tumor-infiltrating lymphocytes (TILs) frequency and response to anti-PD-L1 therapy[2], and validating AT-3, B16, and 4T1 tumors as models for poorly T cell-infiltrated tumors refractory to anti-PD-L1 therapy
Summary
The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Despite unprecedented clinical activity across multiple types of cancer with programmed death 1 (PD-1)/ligand[1] (PD-L1) blockade therapy, the majority of patients do not respond (primary resistance) or develop resistance after initial tumor regression (acquired resistance)[1] This is due, at least in part, to poor T cell infiltration into the tumor, which is negatively correlated with treatment response[2]. The development of novel approaches to increase T cell infiltration within the tumor microenvironment (TME) is of paramount importance and likely would markedly increase the number of patients benefiting from immunotherapy To this point, compelling evidence indicates critical roles for tumor-residing Batf3-dependent conventional type-1 dendritic cells (cDC1s) (migratory CD103+ and lymphoid CD8a+ DCs in mice, and CD141+ DCs in humans) in priming and expansion of tumorspecific CD8+ T cells[3,4,5,6,7,8] and their recruitment to the TME9. Combined TLR/CD40 stimulation synergistically enhances CD8+ T cell expansion[21], and mediates potent antitumor immunity in multiple syngeneic mouse models[22,23,24]
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