Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients

Abstract

Background:Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined.Methods:Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated.Results:A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression.Conclusions:IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.

Comparisons between tumor burden and other prognostic factors that influence survival of patients with non‐small cell lung cancer treated with immune checkpoint inhibitors

“…Although many biomarkers for ICI treatment have been previously verified, most cannot be used in the real‐world clinical setting because they require specialized equipment or are too expensive to analyze. A recent study explored prognostic indexes based on pretreatment derived neutrophil‐to‐lymphocyte ratios and lactate dehydrogenase in patients with advanced NSCLC treated with ICIs …”

“…Immune checkpoint inhibitors (ICIs), specifically programmed cell death 1 (PD‐1)/PD‐1 ligand (PD‐L1) inhibitors, have remarkable efficacy against advanced non‐small cell lung cancer (NSCLC) . Various predictive biomarkers for the response to ICIs have been previously reported, such as tumor mutation burden, mismatch repair and DNA replication genes, tumor microenvironment, immune gene signature, interferon‐γ related mRNA‐based signatures, peripheral blood biomarkers, myeloid‐derived suppressor cells, and lactate dehydrogenase (LDH) level . However, in the real‐world clinical setting, biomarkers that are available before starting treatment are limited.…”

Interferon gamma in cancer immunotherapy

“…Higgs et al found that in patients with metastasized NSCLC and urothelial cancer who have been received PD‐L1 inhibitor (durvalumab), an increased IFNγ gene signature ( IFNγ, CD274, LAG3, and CXCL9 ) is correlated with higher overall response rates and longer median progression‐free survival, which is independent of PD‐L1 expression assessed by immunohistochemistry, suggesting that IFNγ gene signature may stratify patients with improved outcomes to anti‐PD‐L1 antibodies. Furthermore, one recent report showed that PD‐1 inhibitor treatment of NSCLC patients and melanoma patients leads to higher IFNγ protein expression, accompanying with significantly longer progression‐free survival, indicating that IFNγ could be a biomarker for prediction of response to immune checkpoint blockade. However, in patients with locally advanced lung adenocarcinoma, tumor‐expressing IFNγ alone has no significant prognostic value, while tumor‐expressing both IFNγ and PD‐L1 have the best value .…”

T lymphocyte subsets in cancer immunity: Friends or foes

“…In fact, progression‐free survival was better in melanoma and lung cancers with high expression levels of IFN‐γ. In addition, a significantly longer overall survival was observed in the case of melanoma . Thus, Th1 cell related responses are mainly beneficial in terms of mounting an efficient antitumor immune response and are therefore associated to a good outcome for patients in numerous cancer types.…”