CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development

Abstract

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRAS G12V or EGFR L858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (T regs ), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.

Distinct circulating cytokine/chemokine profiles correlate with clinical benefit of immune checkpoint inhibitor monotherapy and combination therapy in advanced non‐small cell lung cancer

“…Dysfunction of cytokines and chemokines (e.g., IL‐1β, IL‐6, IL‐10, CCL2, CCL5) in TME of lung cancer were able to activate the tumor cell and inflammatory cell through signal pathway family such as nuclear factor‐kappa B (NF‐κB) family and signal transducer and activator of transcription (STAT) family which may lead to tumor immune escape, tumor angiogenesis, epithelial‐to‐transition (EMT) and anti‐apoptosis in lung cancer 42–44 . In addition, CCL5 can decreased regulatory T cells (Tregs) through MAPK activation and promote an immune suppressive lung cancer environment 45 . It was reported that under the stimulation of IL‐17A, the process of migration, invasion, and EMT can be promoted by NLRP3 activation in lung cancer 46 .…”

“…According to RECIST v1.1, the number of patients evaluated as CR, PR, SD, or PD was 1 (2.0%), 19 (37.3%), 13 (25.5%), and 18 (35.3%), respectively. Patients were then categorized as DCB (28, 54.9%) or NDB (23,45.1%) according to the criteria described Section 2 and elsewhere. [33][34][35] The clinical features have been summarized in Table 1.…”

Immune infiltration landscape on prognosis and therapeutic response and relevant epigenetic and transcriptomic mechanisms in lung adenocarcinoma

“…A higher TMB score was observed in C1, demonstrating that this subgroup might be responsive to ICB. Oncogenic mutations are usually regarded as driving factors of tumorigenesis via tumor cell-intrinsic mechanisms (35). LUAD exhibits the traits of a high mutational rate of driver genes.…”

“…Oncogenic mutations are usually regarded as driving factors of tumorigenesis via tumor cell-intrinsic mechanisms ( 35 ). LUAD exhibits the traits of a high mutational rate of driver genes.…”

Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments

“…Both CCL5 and CCL22 were associated with the recruitment of Tregs, which may induce the exhaustion of CD8+ T cells. A prominent temporal increase of CCL5 was also demonstrated in EGFR-MT through increased MAPK/ERK signaling ( 81 ). The CCL22 was also elevated in EGFR-MT via JNK/c-Jun activation ( 22 ).…”