{
  "abstract": "Background Immune checkpoint blockade (ICB) has revolutionized cancer therapy, yet resistance—both primary and acquired—remains a significant obstacle, affecting the majority of patients.Methods Here, we leverage a large-scale, real-world clinicogenomic dataset to systematically explore the molecular underpinnings of ICB resistance in the post-progression setting. We analyze over 5,000 pan-cancer patients with clinical and pre-/post-treatment genomic and transcriptomic data and systematically compare the clinical and molecular features of acquired versus primary ICB resistance.Results Post-ICB progression, acquired resistance showed extended survival compared to primary resistance across all cancer types. This clinical phenotype was paralleled by a universally immune-inflamed, albeit dysfunctional, tumor microenvironment (TME) at the onset of acquired resistance, with sustained or ICB-induced inflammatory and interferon responses. We confirm previously described mechanisms of acquired resistance, including B2M loss-of-function (LoF) in non-small cell lung cancer (NSCLC), and identify novel potential mediators, including LoF of TGFBR2 in NSCLC, CYLD in head and neck cancer, and RUNX1 in triple-negative breast cancer. Further supporting their involvement in resistance, these acquired ICB alterations associated with immune-escaped TMEs, characterized by active immunomodulatory oncogenic signaling, hyperproliferation and invasiveness, or altered tumor metabolism.Conclusions These findings emphasize the heterogeneity of molecular drivers of acquired resistance to ICB within and across cancers, and highlight the potential for personalized therapeutic interventions post-progression to improve patient outcomes.",
  "authors": [
    {
      "affiliations": [
        "Oncology Data Science and AI, Oncology R&D, AstraZeneca Cambridge Biomedical Campus, Cambridge, UK"
      ],
      "name": "Mohamed Reda Keddar"
    },
    {
      "affiliations": [
        "Boehringer Ingelheim USA, Ridgefield, Connecticut, USA"
      ],
      "name": "Sebastian Carrasco Pro"
    },
    {
      "affiliations": [
        "Late Development Oncology, AstraZeneca R&D Cambridge, Cambridge, UK"
      ],
      "name": "Roy Rabbie"
    },
    {
      "affiliations": [
        "Quotient Therapeutics, Cambridge, UK"
      ],
      "name": "Zeynep Kalender Atak"
    },
    {
      "affiliations": [
        "Oncology Data Science and AI, Oncology R&D, AstraZeneca, Barcelona, Spain"
      ],
      "name": "Francesc Muyas"
    },
    {
      "affiliations": [
        "Oncology Data Science and AI, Oncology R&D, AstraZeneca Cambridge Biomedical Campus, Cambridge, UK"
      ],
      "name": "Ana Camelo Stewart"
    },
    {
      "affiliations": [
        "Oncology Research and Development, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Scott A Hammond"
    },
    {
      "affiliations": [
        "Oncology Research and Development, AstraZeneca, Gaithersburg, Maryland, USA"
      ],
      "name": "Doug C Palmer"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Ross Stewart"
    },
    {
      "affiliations": [
        "Tempus, Chicago, Illinois, USA"
      ],
      "name": "Maureen Carey"
    },
    {
      "affiliations": [
        "Tempus, Chicago, Illinois, USA"
      ],
      "name": "Kathleen Burke"
    },
    {
      "affiliations": [
        "Biorelate, Manchester, UK"
      ],
      "name": "Ben Sidders"
    },
    {
      "affiliations": [
        "Oncology Data Science and AI, Oncology R&D, AstraZeneca, Barcelona, Spain"
      ],
      "name": "Jessica Davies"
    },
    {
      "affiliations": [
        "Tempus, Chicago, Illinois, USA"
      ],
      "name": "Jonathan R Dry"
    },
    {
      "affiliations": [
        "Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Inigo Martincorena"
    },
    {
      "affiliations": [
        "Oncology Data Science and AI, Oncology R&D, AstraZeneca Cambridge Biomedical Campus, Cambridge, UK"
      ],
      "name": "Sajan Khosla"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Adam Schoenfeld"
    },
    {
      "affiliations": [
        "GSK R&D Stevenage, Stevenage, UK"
      ],
      "name": "Martin L Miller"
    }
  ],
  "title": "Pan-cancer analysis in the real-world setting uncovers immunogenomic drivers of acquired resistance post-immunotherapy",
  "uid": "658141ab-5875-53cd-a62f-b978724b3541"
}