The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
Cancer Cell. 2021 Dec 13;39(12):1594-1609.e12. doi: 10.1016/j.ccell.2021.10.009. Epub 2021 Nov 11.
Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1CXCL13 activated T cells, IgG plasma cells, and SPP1 macrophages, referred to as the lung cancer activation module (LCAM). We confirmed LCAM enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAM lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.
免疫疗法是非小细胞肺癌（NSCLC）治疗的主要方法。虽然肿瘤突变负担（TMB）与免疫治疗反应相关，但对于基线免疫反应与肿瘤基因型之间的关系知之甚少。我们使用单细胞 RNA 测序技术，对 35 个早期 NSCLC 病变中的 361929 个细胞进行了分析。我们鉴定了一个由 PDCD1+CXCL13+激活的 T 细胞、IgG 浆细胞和 SPP1+巨噬细胞组成的细胞模块，称为肺癌激活模块（LCAM）。我们在多个 NSCLC 队列中证实了 LCAM 的富集，并通过配对的 CITE-seq 建立了一个抗体面板来识别 LCAM 病变。LCAM 的存在与 TMB、癌症睾丸抗原和 TP53 突变相关，与总免疫细胞含量无关。高基线 LCAM 评分与 NSCLC 对免疫治疗的增强反应相关，即使在 TMB 高于中位数的患者中也是如此，这表明免疫细胞组成虽然与 TMB 相关，但可能是免疫治疗反应的一个非冗余生物标志物。
