Medical Oncology Department, Grupo Carinho de Clínicas Oncológicas, São José dos Campos, Brazil.
Translational Immuno-oncology Laboratory, Albert Einstein Research and Education Center, Hospital Israelita Albert Einstein, São Paulo, Brazil.
Front Immunol. 2022 Aug 24;13:984349. doi: 10.3389/fimmu.2022.984349. eCollection 2022.
Lung cancer is the second most common and the most lethal malignancy worldwide. It is estimated that lung cancer in never smokers (LCINS) accounts for 10-25% of cases, and its incidence is increasing according to recent data, although the reasons remain unclear. If considered alone, LCINS is the 7th most common cause of cancer death. These tumors occur more commonly in younger patients and females. LCINS tend to have a better prognosis, possibly due to a higher chance of bearing an actionable driver mutation, making them amenable to targeted therapy. Notwithstanding, these tumors respond poorly to immune checkpoint inhibitors (ICI). There are several putative explanations for the poor response to immunotherapy: low immunogenicity due to low tumor mutation burden and hence low MANA (mutation-associated neo-antigen) load, constitutive PD-L1 expression in response to driver mutated protein signaling, high expression of immunosuppressive factors by tumors cells (like CD39 and TGF-beta), non-permissive immune TME (tumor microenvironment), abnormal metabolism of amino acids and glucose, and impaired TLS (Tertiary Lymphoid Structures) organization. Finally, there is an increasing concern of offering ICI as first line therapy to these patients owing to several reports of severe toxicity when TKIs (tyrosine kinase inhibitors) are administered sequentially after ICI. Understanding the biology behind the immune response against these tumors is crucial to the development of better therapeutic strategies.
肺癌是全球第二大常见且最致命的恶性肿瘤。据估计，从不吸烟者肺癌（LCINS）占病例的 10-25%，根据最近的数据，其发病率正在上升，尽管原因尚不清楚。如果单独考虑，LCINS 是第七大常见的癌症死因。这些肿瘤更常见于年轻患者和女性。LCINS 倾向于有更好的预后，可能是由于更高的机会携带可操作的驱动突变，使其能够接受靶向治疗。尽管如此，这些肿瘤对免疫检查点抑制剂（ICI）的反应不佳。对于免疫治疗反应不佳有几种推测的解释：由于肿瘤突变负担低，因此 MANA（突变相关新抗原）负荷低，导致免疫原性低，由于驱动突变蛋白信号导致组成性 PD-L1 表达，肿瘤细胞高表达免疫抑制因子（如 CD39 和 TGF-β），非允许性免疫 TME（肿瘤微环境），氨基酸和葡萄糖代谢异常，以及 TLS（三级淋巴结构）组织受损。最后，由于在 ICI 后序贯给予 TKI（酪氨酸激酶抑制剂）时会发生严重毒性的报道越来越多，人们越来越担心将 ICI 作为一线治疗方法用于这些患者。了解这些肿瘤免疫反应背后的生物学对于开发更好的治疗策略至关重要。
