Immune checkpoint inhibitors1 result in impressive clinical responses2–5 but optimal results will require combination with each other6 and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio. RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion. Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.
SUMMARY Therapeutic blocking of the PD1 pathway results in significant tumor responses but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways, and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T cell therapy. Mechanisms driving immunosuppression and poor T cell infiltration in PDA are incompletely understood. Here we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy (RT) and ICB with αCTLA-4 and αPD-1. The combination of an agonist αCD40 antibody, RT, and dual ICB eradicated irradiated and unirradiated (i.e. abscopal) tumors, generating long-term immunity. Response required T cells and also short-lived myeloid cells and was dependent on the long non-coding RNA myeloid regulator Morrbid. Using unbiased random forest machine learning, we built unique, contextual signatures for each therapeutic component, revealing that (i) RT triggers an early proinflammatory stimulus, ablating existing intratumoral T cells and upregulating MHC class I and CD86 on antigen presenting cells, (ii) αCD40 causes a systemic and intratumoral reorganization of the myeloid compartment, and (iii) ICB increases intratumoral T cell infiltration and improves the CD8 T cell:regulatory T cell ratio. Thus, αCD40 and RT non-redundantly augment anti-tumor immunity in PDA, which is otherwise refractory to ICB, providing a clear rationale for clinical evaluation.
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