Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s
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PROVIDER: PRJNA647616 | ENA |
REPOSITORIES: ENA
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Project description:T-cell exclusion from the tumor microenvironment (TME) is a significant obstacle in cancer immunotherapy. Evidence indicates crucial roles of Batf3-dependent dendritic cells for inducing antitumor T-cell immunity. However, strategies to maximize the engagement of Batf3-dependent dendritic cells into such ‘cold tumors’ remain elusive. Using multiple syngeneic orthotopic mouse models of non-T cell-inflamed tumors, we hypothesized that in situ induction and activation of tumor-residing Batf3-dependent dendritic cells 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 robust regression not only of primary, but also untreated distant tumors, and renders non-T cell-inflamed tumors responsive to anti-PD-L1 therapy. Furthermore, serial ISIM reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, resulting in eradication of tumors, and establishes tumor-specific immunological memory. These findings provide new insights into Batf3-dependent dendritic cells biology as a critical determinant to the formation of a T cell-inflamed TME.
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Project description: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.
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Project description:MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby modulating activation of co-cultured T cells. During MAPKi therapy in vivo, tumor cell-intrinsic ITCH knockdown in murine melanoma induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-proficient mice. Conversely, tumor cell-intrinsic ITCH over-expression reduced MAPKi-elicited PD-L1 accumulation, augmented cytolytic CD8+ T-cell infiltration, and suppressed acquired resistance in BrafMUT, NrasMUT, and Nf1MUT murine melanoma and KrasMUT pancreatic cancer models. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 over-expression nullified the ability of ITCH over-expression to suppress MAPKi-resistance, supporting in vivo the ITCH–PD-L1–T-cell regulatory axis demonstrated in human cancer cell lines. Moreover, we identified a small-molecular ITCH activator which suppressed acquired MAPKi-resistance in vivo. Thus, MAPKi-elicited tumor-surface PD-L1 accelerates acquired-resistance, and degrading PD-L1 by activating ITCH may be a combinatorial approach to promote antitumor T-cell immunity and durable responses.
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Project description:Immune tolerance is an active state of unresponsiveness of the immune system to antigens (Ags) that have the potential to induce an immune response1. Such tolerance is beneficial in avoiding autoimmunity and rejection of organ transplants, but detrimental in cancer2. Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis3 and cross-presenting abilities4, resulting in T cell-mediated immunity5 or tolerance6-10. However, the mechanisms underlying the tolerogenic function of cDC1s remain largely unknown. Here, we show that the erythropoietin receptor (EpoR) acts as a critical switch that determines the tolerogenic state of cDC1s and the threshold of Ag-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance11,12, EpoR+ cDC1s induce donor-specific CD4+FoxP3+ regulatory T cells (Tregs), and conditional knockout of EpoR in cDC1s abrogates Ag-specific Treg induction, resulting in allograft rejection. In the steady state, EpoR+ migratory cDC1s control Ag-specific Treg induction in peripheral lymph nodes (LNs). In cancer, EpoR is expressed on both tumor Ag-carrying, tumor-infiltrating cDC1s, as well as migratory cDC1s in tumor-draining LNs (tdLNs). Loss of EpoR from cDC1s leads to tumor reduction by enhancing tumor Ag-specific CD8+ T cell priming and generating more precursor exhausted T cells13 in tdLNs, preserving CD8+ T cell precursor-like features and effector function, and reducing Tregs in the tumor. Thus, targeting EpoR on cDC1s to induce or inhibit immune tolerance should enable new ways to treat a variety of diseases.
2024-03-01 | GSE253056 | GEO
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE
Project description:To investigate a possible candidate for overcoming the acquired resistance to ALK-TKI, we established an in vitro model of acquired resistance to crizotinib (H3122-CR) by exposing EML4-ALK–positive H3122 lung cancer cells to increasing doses of crizotinib.
2019-12-31 | GSE117181 | GEO
Project description:Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance
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Project description:To assess genotypic differences between IL-33-induced CD103+ cDC1s and GM-CSF-induced CD103+ cDC1s IL-33 or GM-CSF was treated at 5 ng/ml on the day 5 of Flt3L-BMDC generation and then the cells were incubated for an additional 5 days Then, we performed RNA sequencing of CD103+ cDC1s isolated from IL-33 or GM-CSF-treated Flt3L-BMDCs
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