Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance

Abstract

Background Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of lung squamous cell carcinoma (LUSC). However, a significant proportion of patients with high tumour PD-L1 expression remain resistant to immune checkpoint inhibitors. To understand the underlying resistance mechanisms, characterization of the immunosuppressive tumour microenvironment and identification of biomarkers to predict resistance in patients are urgently needed. Methods Our study retrospectively analysed RNA sequencing data of 624 LUSC samples. We analysed gene expression patterns from tumour microenvironment by unsupervised clustering. We correlated the expression patterns with a set of T cell exhaustion signatures, immunosuppressive cells, clinical characteristics, and immunotherapeutic responses. Internal and external testing datasets were used to validate the presence of exhausted immune status. Results Approximately 28 to 36% of LUSC patients were found to exhibit significant enrichments of T cell exhaustion signatures, high fraction of immunosuppressive cells (M2 macrophage and CD4 Treg), co-upregulation of 9 inhibitory checkpoints (CTLA4, PDCD1, LAG3, BTLA, TIGIT, HAVCR2, IDO1, SIGLEC7, and VISTA), and enhanced expression of anti-inflammatory cytokines (e.g. TGFβ and CCL18). We defined this immunosuppressive group of patients as exhausted immune class (EIC). Although EIC showed a high density of tumour-infiltrating lymphocytes, these were associated with poor prognosis. EIC had relatively elevated PD-L1 expression, but showed potential resistance to ICB therapy. The signature of 167 genes for EIC prediction was significantly enriched in melanoma patients with ICB therapy resistance. EIC was characterized by a lower chromosomal alteration burden and a unique methylation pattern. We developed a web application (http://lilab2.sysu.edu.cn/tex & http://liwzlab.cn/tex) for researchers to further investigate potential association of ICB resistance based on our multi-omics analysis data. Conclusions We introduced a novel LUSC immunosuppressive class which expressed high PD-L1 but showed potential resistance to ICB therapy. This comprehensive characterization of immunosuppressive tumour microenvironment in LUSC provided new insights for further exploration of resistance mechanisms and optimization of immunotherapy strategies.

Prognostic Value and Genome Signature of m6A/m5C Regulated Genes in Early-Stage Lung Adenocarcinoma

“…The m6A/m5C modification could regulate the immune checkpoint molecular expression and affect the activation of antitumor immune cells. Taken together, the above immune features in Cluster2 exhibited a T cells exhaustion state alongside the loss of the effector function, characterized by a high expression of immune checkpoint genes, chemokine and chemokine receptor genes, and immune cells, such as T cells, CD8+ T cells, cytotoxic lymphocytes, NK cells, and so on [ 20 , 21 ]. In addition, some studies found that epigenetic modification changes were involved in the exhaustion progress, which implied the correlation between m6A/m5C epigenetic modification genes and the loss of the immune effector, which contributed to poor survival outcomes [ 22 ].…”

Cuproptosis-related molecular subtypes direct T cell exhaustion phenotypes and therapeutic strategies for patients with lung adenocarcinoma

“…Subsequently, checkpoint genes, transcription, and inflammatory factors associated with TEX were further analyzed in different molecular subtypes. Nine checkpoint genes such as PDCD1 , CTLA4 , HAVCR2 , TIGIT , LAG3 , IDO1 , SIGLEC7 , CD274 , PDCD1LG2 were chosen as TEX-associated checkpoint genes ( Yang et al, 2022 ). Furthermore, eleven transcription factors, including TOX , TBX21 , EOMES , BATF , NFATC1-4 , NR4A1 -3, as well as seven inflammatory factors such as IL1RN , IL4 , IL10 , CCL18 , TGFB1 , IL1B , CCL2 were employed to evaluate the TEX progress ( Zheng et al, 2021 ; Zhang et al, 2022 ).…”

Landscapes and mechanisms of CD8+ T cell exhaustion in gastrointestinal cancer

“…In the early stages of tumor development, i.e., before sufficient numbers of cancer cells and tumor antigens form and/or appear, tumor-reactive CD8 + T cells may remain in a state of ignorance (26,27). As cancer progresses, CD8 + T cells are continuously stimulated by tumor antigens and enter a late dysfunctional state late (28).Exhausted-like T cells isolated in progressive tumors will exhibit tumor-infiltrating lymphocytes (TIL) that are responsive to tumor antigens expressing multiple inhibitory receptors and failing to produce effector cytokines or cytotoxic molecules (29)(30)(31)(32). The mechanism that CD8 +T cells cannot eliminate cancer is attributed to factors such as cancer cells and TME, etc.…”