Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients

• Published in: Journal of cancer research and clinical oncology 2017-09, Vol.143 (9), p.1745-1756
• Main Authors: Bhat, Shreyas, Gardi, Nilesh, Hake, Sujata, Kotian, Nirupama, Sawant, Sharada, Kannan, Sadhana, Parmar, Vani, Desai, Sangeeta, Dutt, Amit, Joshi, Narendra N.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers, Tumor - immunology; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Cancer Research; Cytokines; Female; Gene expression; Hematology; Humans; Immunosuppression; Inflammation; Interleukin 1; Interleukin 21; Interleukin 23; Interleukin-17 - biosynthesis; Interleukin-17 - immunology; Interleukins - biosynthesis; Interleukins - immunology; Internal Medicine; Lymph; Lymph nodes; Lymphatic Metastasis - immunology; Lymphatic Metastasis - pathology; Lymphatic system; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Metastases; Middle Aged; Natural killer cells; Oncology; Original Article – Cancer Research; T-Lymphocytes - immunology; Transcription; Transcriptome; Tumors
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-017-2431-5

Purpose Pro-inflammatory cytokines such as Interleukin-17A (IL17A) and Interleukin-32 (IL32), known to enhance natural killer and T cell responses, are also elevated in human malignancies and linked to poor clinical outcomes. To address this paradox, we evaluated relation between IL17A and IL32 expression and other inflammation- and T cell response-associated genes in breast tumors. Methods TaqMan-based gene expression analysis was carried out in seventy-eight breast tumors. The association between IL17A and IL32 transcript levels and T cell response genes, ER status as well as lymph node status was also examined in breast tumors from TCGA dataset. Results IL17A expression was detected in 32.7% ER-positive and 84.6% ER-negative tumors, with higher expression in the latter group (26.2 vs 7.1-fold, p < 0.01). ER-negative tumors also showed higher expression of IL32 as opposed to ER-positive tumors (8.7 vs 2.5-fold, p < 0.01). Expression of both IL17A and IL32 genes positively correlated with CCL5, GNLY, TBX21, IL21 and IL23 transcript levels ( p < 0.01). Amongst ER-positive tumors, higher IL32 expression significantly correlated with lymph node metastases ( p < 0.05). Conversely, in ER-negative subtype, high IL17A and IL32 expression was seen in patients with negative lymph node status ( p < 0.05). Tumors with high IL32 and IL17A expression showed higher expression of TH1 response genes studied, an observation validated by similar analysis in the TCGA breast tumors (n=1041). Of note, these tumors were characterized by low expression of a potentially immunosuppressive isoform of IL32 (IL32γ). Conclusion These results suggest that high expression of both IL17A and IL32 leads to enhancement of T cell responses. Our study, thus, provides basis for the emergence of strong T cell responses in an inflammatory milieu that have been shown to be associated with better prognosis in ER-negative breast cancer.