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 PDCD1⁺CXCL13⁺ activated T cells, IgG⁺ plasma cells, and SPP1⁺ macrophages, referred to as the lung cancer activation module (LCAM^hi). We confirmed LCAM^hi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAM^hi 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) 管理的支柱。虽然肿瘤突变负荷 (TMB) 与对免疫疗法的反应相关，但人们对基线免疫反应与肿瘤基因型之间的关系知之甚少。使用单细胞 RNA 测序，我们分析了来自 35 个早期 NSCLC 病变的 361,929 个细胞。我们确定了一个由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 ^hi )。我们在多个 NSCLC 队列中证实了 LCAM ^hi富集，并且配对的 CITE-seq 建立了一个抗体组来识别 LCAM^喜病灶。发现 LCAM 的存在与整体免疫细胞含量无关，并与 TMB、癌症睾丸抗原和TP53突变相关。高基线 LCAM 评分与增强的 NSCLC 对免疫疗法的反应相关，即使在 TMB 高于中值的患者中也是如此，这表明免疫细胞组成虽然与 TMB 相关，但可能是免疫疗法反应的非冗余生物标志物。