Nie Yunan, Schalper Kurt A, Chiang Anne
Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA.
Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
Cancer Drug Resist. 2024 Dec 28;7:55. doi: 10.20517/cdr.2024.154. eCollection 2024.
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a poor prognosis. Although the addition of immunotherapy to chemotherapy has modestly improved outcomes, most patients rapidly develop resistance. Resistance to immunotherapy can be broadly categorized into primary resistance and acquired resistance, as proposed by the Society for Immunotherapy of Cancer (SITC) consensus definition. Primary resistance occurs in the setting of failure to respond to immune checkpoint inhibitors (ICIs), while acquired resistance develops after initial response. The mechanisms of acquired and primary resistance to ICI are not well understood in SCLC, denoting an area of critical unmet need. Both intrinsic and extrinsic mechanisms play significant roles in immunotherapy resistance. Intrinsic mechanisms include defects in antigen presentation, mutations in key genes, reduced tumor immunogenicity, and epigenetic alterations. Extrinsic mechanisms involve the tumor microenvironment (TME), which is a complex interplay of both tumor- and immunosuppressive immune cells, vasculature, and microbiome. An understanding of these resistance mechanisms is crucial for developing novel therapeutic strategies to advance effective immunotherapy in patients with SCLC, a critical area of unmet need.
小细胞肺癌（SCLC）是一种侵袭性神经内分泌肿瘤，预后较差。尽管在化疗基础上加用免疫疗法已适度改善了治疗结果，但大多数患者会迅速产生耐药性。根据癌症免疫治疗学会（SITC）的共识定义，对免疫疗法的耐药性可大致分为原发性耐药和获得性耐药。原发性耐药发生在对免疫检查点抑制剂（ICI）无反应的情况下，而获得性耐药则在初始反应后出现。在SCLC中，对ICI获得性和原发性耐药的机制尚未完全了解，这表明存在一个关键的未满足需求领域。内在和外在机制在免疫治疗耐药中都起着重要作用。内在机制包括抗原呈递缺陷、关键基因突变、肿瘤免疫原性降低和表观遗传改变。外在机制涉及肿瘤微环境（TME），它是肿瘤免疫细胞和免疫抑制细胞、脉管系统和微生物群之间复杂的相互作用。了解这些耐药机制对于开发新的治疗策略以推进SCLC患者的有效免疫治疗至关重要，这是一个关键的未满足需求领域。
