A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response

Author:

Kar Animesh1ORCID,Jain Dolly1ORCID,Kumar Sandeep1ORCID,Rajput Kajal2ORCID,Pal Sanjay1ORCID,Rana Kajal1ORCID,Kar Raunak3ORCID,Jha Somesh K.1ORCID,Medatwal Nihal2ORCID,Yavvari Prabhu Srinivas4ORCID,Pandey Nishant1ORCID,Mehta Devashish2ORCID,Sharma Harsh2ORCID,Bhattacharya Debanjan5ORCID,Pradhan Manas K.4ORCID,Sharma Ravi Datta2ORCID,Srivastava Aasheesh4ORCID,Agrawal Usha5ORCID,Mukhopadhyay Arnab3ORCID,Sengupta Sagar36ORCID,Patil Veena S.3,Bajaj Avinash1ORCID,Dasgupta Ujjaini2ORCID

Affiliation:

1. Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India.

2. Amity Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon, 122413, Haryana, India.

3. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.

4. Department of Chemistry, Indian Institute of Science Education and Research, Bhopal, 462066, Madhya Pradesh, India.

5. National Institute of Pathology, Safdarjung Hospital Campus, Ansari Nagar West, New Delhi, 110029, India.

6. National Institute of Biomedical Genomics, Kalyani, 741251, West Bengal, India.

Abstract

Treatment of triple-negative breast cancer (TNBC) is challenging because of its “COLD” tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B + CD8 + T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)–like endoplasmic reticulum kinase (PERK)–mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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