Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer

Abstract

The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4+ T cells that express a canonical cytotoxic gene program and NSCLC cells with elevated HLA-II expression. We postulate cytotoxic CD4+ T cells mediate anti-tumor activity via HLA-II on tumor cells and augment HLA-I-dependent cytotoxic CD8+ T cell interactions to drive ICB response in NSCLC. We show that integrating tumor extrinsic cytotoxic gene expression with tumor mutational burden is associated with longer time to progression in a real-world cohort of 123 NSCLC patients treated with ICB regimens, including those with HLA-LOH.

Novel EGFR-Mutant Mouse Models of Lung Adenocarcinoma Reveal Adaptive Immunity Requirement for Durable Osimertinib Response

“…We previously reported that the degree of induction of the IFNγ Hallmark response as well as a T cell signature [49] in on-treatment biopsies associate with the duration of therapeutic benefit in patients bearing EGFR mutant lung cancers [18]. Herein, we demonstrate that the magnitude of two additional gene expression signatures previously shown to predict responsiveness to anti-PD-1-based immune therapy [42, 43] also associate with longer time to progression on EGFR TKIs ( Figure 1 ). Thus, there is ample evidence for immune engagement by human EGFR mutant lung cancers despite their lack of sensitivity to anti-PD-1 therapies [44-46], a feature that is shared by orthotopic tumors derived from the murine EGFR mutant cell lines (data not shown).…”

“…Using previously reported RNAseq data from pre- and on-treatment biopsies collected from EGFR mutant LUAD patients, the sums of the 18 genes in the signature described by (A) Ayers et al [42] and the 25 genes in the signature described by (B) Lau et al [43] were calculated for each patient-derived specimen and converted to Z-scores. The resulting values for the Ayers ( A ) and Lau et al ( B ) signatures were binned by TTP of less than or greater than 12 months where the eight patients exhibited TTP of 6, 6.2, 8.3, 8.6 12.5, 13, 13.1 and 16.3 months (mean and median = 10.5 and 10.6 months, respectively).…”

“…The findings revealed induction of multiple immune and inflammation-related pathways in "on-treatment" relative to pre-treatment biopsies, and the degree of induction of the IFNg Hallmark pathway was positively associated with the time to progression (TTP) experienced by the patients. The RNAseq data were used to calculate scores from the T cell-inflamed gene expression profile reported by Ayers et al [42] as well as a cytotoxic T cell signature developed by Lau et al [43]. Both of these signatures were found to associate with response to anti-PD-1 immunotherapy.…”

“…Future studies will be directed at characterizing the progressing tumors in the immunodeficient hosts. from pre-and on-treatment biopsies collected from EGFR mutant LUAD patients, the sums of the 18 genes in the signature described by (A) Ayers et al [42] and the 25 genes in the signature described by (B) Lau et al [43] were calculated for each patient-derived specimen and converted to Z-scores. The resulting values for the Ayers The tumor-bearing mice were submitted to weekly µCT scans and the data are presented as fold of the initial pre-treatment volumes (means and SEM).…”

Immune biology of NSCLC revealed by single-cell technologies: implications for the development of biomarkers in patients treated with immunotherapy

“…Lau et al [ 63 ] demonstrated that NSCLC tumor cells expressed human leucocyte antigen (HLA)-II transcripts, mainly HLA-DRB1. Besides, they identified a cluster of cytotoxic GZMB CD4 + T cells that expressed high levels of PDCD1 and CTLA4, suggesting that this population could be involved in the anti-tumor response after immunotherapy.…”