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

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

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.

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Abbreviations

IL:

Interleukin

ER:

Estrogen receptor

LN:

Lymph node

CRI:

Cancer-related inflammation

CTLs:

Cytotoxic T lymphocytes

Th:

T helper

Tc:

T cytotoxic

PCR:

Polymerase chain reaction

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Acknowledgements

This work was supported by Grant from the Department of Biotechnology, Ministry of Science and Technology, Government of India. The authors would like to thank Mrs. Manisha Kulkarni and Mr. Anand Deshpande at ICMR National Tumor Tissue Repository at TMH and Dr. Kishore Amin and Mr. Madan Ludbe at tumor tissue repository at ACTREC. Help provided by Dr. Sridhar, Consultant Pathologist, ACTREC, and Mrs. Pallavi Rane, ECTU, CRC, ACTREC is gratefully acknowledged.

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Authors and Affiliations

  1. Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Shreyas Bhat, Nilesh Gardi, Sujata Hake, Nirupama Kotian, Sharada Sawant, Amit Dutt & Narendra N. Joshi

  2. Epidemiology and Clinical Trials Unit, Clinical Research Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India

    Sadhana Kannan

  3. Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India

    Vani Parmar

  4. Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, 400012, India

    Sangeeta Desai

  5. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, Maharashtra, India

    Nilesh Gardi, Vani Parmar, Sangeeta Desai, Amit Dutt & Narendra N. Joshi

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  1. Shreyas Bhat
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Correspondence to Narendra N. Joshi.

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Funding

This study was funded by Department of Biotechnology, Government of India (Grant Number BT/PR10199/Med/30/68/2007).

Conflict of interest

All authors declares that they have no conflict of interest.

Animal study

This article does not contain any studies with animals performed by any of the authors.

Ethical approval for studies in patients

All the procedures involving human participants were performed in accordance with the ethical standards of the institutional and national research committees (guidelines) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

432_2017_2431_MOESM1_ESM.jpg

Supplementary Figure S1. Expression levels of IL17A and IL32 transcripts in tumors studied in the TCGA database (JPEG 273 kb)

432_2017_2431_MOESM2_ESM.jpg

Supplementary Figure S2. Analysis of expression of T cell response associated genes in ER positive and ER negative breast tumors from the TCGA database grouped on the basis of combinations of expression levels of IL17A and IL32 transcripts. In IL17AposIL32lo group, data for only one ER negative subject was available hence expression levels were not compared (JPEG 267 kb)

432_2017_2431_MOESM3_ESM.jpg

Supplemntary Figure S3 A. Comparison of IL-32 isoform expression levels in ER positive (S3A) tumors. Levels of IL32 isoforms, IL32α, IL32β, IL32γ and IL32ε transcripts were studied using custom designed TaqMan assays obtained from Thermofisher, for individual isoforms as follows: AII1ONV: NM_001012631 (IL-32β); AIMSI6 J:NM_001308078 (IL-32γ); AILJK0B:NM_001012636 (IL-32δ); AIN1HCR:NM_001012634 (IL-32ε). PUM1 (Hs 00472881_ml) was used as endogenous control for the studies and expression levels were normalized and computed relative to the levels of the endogenous control (JPEG 420 kb)

432_2017_2431_MOESM4_ESM.jpg

Supplemntary Figure S3 B. Comparison of IL-32 isoform expression levels in ER negative tumors (S3B). Levels of IL32 isoforms, IL32α, IL32β, IL32γ and IL32ε transcripts were studied using custom designed TaqMan assays obtained from Thermofisher, for individual isoforms as follows: AII1ONV: NM_001012631 (IL-32β); AIMSI6 J:NM_001308078 (IL-32γ); AILJK0B:NM_001012636 (IL-32δ); AIN1HCR:NM_001012634 (IL-32ε). PUM1 (Hs 00472881_ml) was used as endogenous control for the studies and expression levels were normalized and computed relative to the levels of the endogenous control (JPEG 401 kb)

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Bhat, S., Gardi, N., Hake, S. et al. Impact of intra-tumoral IL17A and IL32 gene expression on T-cell responses and lymph node status in breast cancer patients. J Cancer Res Clin Oncol 143, 1745–1756 (2017). https://doi.org/10.1007/s00432-017-2431-5

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