Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers
Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a significant challenge to effectively manage in the clinic worldwide. Immunotherapy may be beneficial to TNBC patients if responders can be effectively identified. Here we sought to elucidate the immune landscape of TNBCs...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S193652332200170X |
| _version_ | 1811339337442263040 |
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| author | Aruna Korlimarla Hari PS Jyoti Prabhu Chanthirika Ragulan Yatish Patil Snijesh VP Krisha Desai Aju Mathews Sandhya Appachu Ravi B. Diwakar Srinath BS Alan Melcher Maggie Cheang Anguraj Sadanandam |
| author_facet | Aruna Korlimarla Hari PS Jyoti Prabhu Chanthirika Ragulan Yatish Patil Snijesh VP Krisha Desai Aju Mathews Sandhya Appachu Ravi B. Diwakar Srinath BS Alan Melcher Maggie Cheang Anguraj Sadanandam |
| author_sort | Aruna Korlimarla |
| collection | DOAJ |
| description | Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a significant challenge to effectively manage in the clinic worldwide. Immunotherapy may be beneficial to TNBC patients if responders can be effectively identified. Here we sought to elucidate the immune landscape of TNBCs by stratifying patients into immune-specific subtypes (immunotypes) to decipher the molecular and cellular presentations and signaling events of this heterogeneous disease and associating them with their clinical outcomes and potential treatment options. Experimental Design: We profiled 730 immune genes in 88 retrospective Indian TNBC samples using the NanoString platform, established immunotypes using non-negative matrix factorization-based machine learning approach, and validated them using Western TNBCs (n=422; public datasets). Immunotype-specific gene signatures were associated with clinicopathological features, immune cell types, biological pathways, acute/chronic inflammatory responses, and immunogenic cell death processes. Responses to different immunotherapies associated with TNBC immunotypes were assessed using cross-cancer comparison to melanoma (n=504). Tumor-infiltrating lymphocytes (TILs) and pan-macrophage spatial marker expression were evaluated. Results: We identified three robust transcriptome-based immunotypes in both Indian and Western TNBCs in similar proportions. Immunotype-1 tumors, mainly representing well-known claudin-low and immunomodulatory subgroups, harbored dense TIL infiltrates and T-helper-1 (Th1) response profiles associated with smaller tumors, pre-menopausal status, and a better prognosis. They displayed a cascade of events, including acute inflammation, damage-associated molecular patterns, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. On the other hand, immunotype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal immunotypes, and an intermediate prognosis. In contrast to the two T-cell enriched immunotypes, immunotype-3 patients expressed innate immune genes/proteins, including those representing myeloid infiltrations (validated by spatial immunohistochemistry), and had poor survival. Remarkably, a cross-cancer comparison analysis revealed the association of immunotype-1 with responses to anti-PD-L1 and MAGEA3 immunotherapies. Conclusion: Overall, the TNBC immunotypes identified in TNBCs reveal different prognoses, immune infiltrations, signaling, acute/chronic inflammation leading to immunogenic cell death of cancer cells, and potentially distinct responses to immunotherapies. The overlap in immune characteristics in Indian and Western TNBCs suggests similar efficiency of immunotherapy in both populations if strategies to select patients according to immunotypes can be further optimized and implemented. |
| first_indexed | 2024-04-13T18:23:42Z |
| format | Article |
| id | doaj.art-a88adf8242244906823d8dcfed4bdb5f |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-04-13T18:23:42Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-a88adf8242244906823d8dcfed4bdb5f2022-12-22T02:35:19ZengElsevierTranslational Oncology1936-52332022-11-0125101511Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancersAruna Korlimarla0Hari PS1Jyoti Prabhu2Chanthirika Ragulan3Yatish Patil4Snijesh VP5Krisha Desai6Aju Mathews7Sandhya Appachu8Ravi B. Diwakar9Srinath BS10Alan Melcher11Maggie Cheang12Anguraj Sadanandam13St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India; Sri Shankara Cancer Hospital and Research Centre, Bangalore, IndiaSt. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India; Sri Shankara Cancer Hospital and Research Centre, Bangalore, India; Division of Molecular Pathology, The Institute of Cancer Research, London, UKSt. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, IndiaDivision of Molecular Pathology, The Institute of Cancer Research, London, UKDivision of Molecular Pathology, The Institute of Cancer Research, London, UKSt. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, IndiaDivision of Molecular Pathology, The Institute of Cancer Research, London, UKMOSC Medical College, Kolenchery, Kerala, IndiaSri Shankara Cancer Hospital and Research Centre, Bangalore, IndiaSri Shankara Cancer Hospital and Research Centre, Bangalore, IndiaSri Shankara Cancer Hospital and Research Centre, Bangalore, IndiaCentre for Translational Immunotherapy, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKClinical Trials and Statistical Unit, The Institute of Cancer Research, London, UKDivision of Molecular Pathology, The Institute of Cancer Research, London, UK; Centre for Translational Immunotherapy, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK; Centre for Global Oncology, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK; Corresponding author at: Centre for Global Oncology, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK.Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease with a significant challenge to effectively manage in the clinic worldwide. Immunotherapy may be beneficial to TNBC patients if responders can be effectively identified. Here we sought to elucidate the immune landscape of TNBCs by stratifying patients into immune-specific subtypes (immunotypes) to decipher the molecular and cellular presentations and signaling events of this heterogeneous disease and associating them with their clinical outcomes and potential treatment options. Experimental Design: We profiled 730 immune genes in 88 retrospective Indian TNBC samples using the NanoString platform, established immunotypes using non-negative matrix factorization-based machine learning approach, and validated them using Western TNBCs (n=422; public datasets). Immunotype-specific gene signatures were associated with clinicopathological features, immune cell types, biological pathways, acute/chronic inflammatory responses, and immunogenic cell death processes. Responses to different immunotherapies associated with TNBC immunotypes were assessed using cross-cancer comparison to melanoma (n=504). Tumor-infiltrating lymphocytes (TILs) and pan-macrophage spatial marker expression were evaluated. Results: We identified three robust transcriptome-based immunotypes in both Indian and Western TNBCs in similar proportions. Immunotype-1 tumors, mainly representing well-known claudin-low and immunomodulatory subgroups, harbored dense TIL infiltrates and T-helper-1 (Th1) response profiles associated with smaller tumors, pre-menopausal status, and a better prognosis. They displayed a cascade of events, including acute inflammation, damage-associated molecular patterns, T-cell receptor-related and chemokine-specific signaling, antigen presentation, and viral-mimicry pathways. On the other hand, immunotype-2 was enriched for Th2/Th17 responses, CD4+ regulatory cells, basal-like/mesenchymal immunotypes, and an intermediate prognosis. In contrast to the two T-cell enriched immunotypes, immunotype-3 patients expressed innate immune genes/proteins, including those representing myeloid infiltrations (validated by spatial immunohistochemistry), and had poor survival. Remarkably, a cross-cancer comparison analysis revealed the association of immunotype-1 with responses to anti-PD-L1 and MAGEA3 immunotherapies. Conclusion: Overall, the TNBC immunotypes identified in TNBCs reveal different prognoses, immune infiltrations, signaling, acute/chronic inflammation leading to immunogenic cell death of cancer cells, and potentially distinct responses to immunotherapies. The overlap in immune characteristics in Indian and Western TNBCs suggests similar efficiency of immunotherapy in both populations if strategies to select patients according to immunotypes can be further optimized and implemented.http://www.sciencedirect.com/science/article/pii/S193652332200170XTriple-negative breast cancerImmunotherapyImmune subtypesImmune cellsGlobal oncologyIndia |
| spellingShingle | Aruna Korlimarla Hari PS Jyoti Prabhu Chanthirika Ragulan Yatish Patil Snijesh VP Krisha Desai Aju Mathews Sandhya Appachu Ravi B. Diwakar Srinath BS Alan Melcher Maggie Cheang Anguraj Sadanandam Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers Translational Oncology Triple-negative breast cancer Immunotherapy Immune subtypes Immune cells Global oncology India |
| title | Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers |
| title_full | Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers |
| title_fullStr | Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers |
| title_full_unstemmed | Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers |
| title_short | Comprehensive characterization of immune landscape of Indian and Western triple negative breast cancers |
| title_sort | comprehensive characterization of immune landscape of indian and western triple negative breast cancers |
| topic | Triple-negative breast cancer Immunotherapy Immune subtypes Immune cells Global oncology India |
| url | http://www.sciencedirect.com/science/article/pii/S193652332200170X |
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