Irreversible Electroporation Combined with Checkpoint Blockade and TLR7 Stimulation Induces Antitumor Immunity in a Murine Pancreatic Cancer Model

Journal of Cancer Immunology Research, 7(10): 1714-1726, October 2019

Jayanth S. Shankara Narayanan, Partha Ray, Tomoko Hayashi, Thomas C. Whisenant, Diego Vicente, Dennis A. Carson, Aaron M. Miller, Stephen P. Schoenberger and Rebekah R. White

Irreversible electroporation (IRE) is a nonthermal ablation technique that is used clinically in selected patients with locally advanced pancreatic cancer, but most patients develop recurrent distant metastatic disease. We hypothesize that IRE can induce an in situ vaccination effect by releasing tumor neoantigens in an inflammatory context. Using an immunocompetent mouse model, we demonstrated that IRE alone produced complete regression of subcutaneous tumors in approximately 20% to 30% of mice.

Unmasking tumor heterogeneity and clonal evolution by single-cell analysis

Journal of Cancer Metastasis and Treatment, 4:47, 31 August 2018

Xiaoshan Shi, Papia Chakraborty, Amitabha Chaudhuri

The intratumoral heterogeneity orchestrated by the tumor intrinsic and extrinsic mechanisms enable cancers to persist and spread notwithstanding the use of aggressive interventional therapies. The heterogeneity is revealed at multiple levels – at the level of individual tumor cells, in the cellular composition of tumor infiltrates and in the chemical microenvironment in which the cells reside. Deconvoluting the complex nature of the cell types present in the tumor, along with the homo and heterotypic interactions between different cell types can produce novel insights of biological and clinical relevance.

A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity

PLoS ONE, 13:9, 26 September 2018

Snigdha Majumder, Rakshit Shah, Jisha Elias, Yogesh Mistry, Karunakaran Coral, Priyanka Shah, Anand Kumar Maurya, Bharti Mittal, Jason K. D’Silva, Sakthivel Murugan, Lakshmi Mahadevan, Rekha Sathian, V. L. Ramprasad, Papia Chakraborty, Ravi Gupta, Amitabha Chaudhuri, Arati Khanna-Gupta

Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family.

A Computational Approach Identifies Immunogenic Features of Prognosis in Human Cancers

Frontiers in Immunology, Vol. 9, 21 December 2018

Malini Manoharan, Nitin Mandloi, Sushri Priyadarshini, Ashwini Patil, Rohit Gupta, Laxman Iyer, Ravi Gupta and Amitabha Chaudhuri

A large number of tumor intrinsic and extrinsic factors determine long-term survival in human cancers. In this study, we stratified 9120 tumors from 33 cancers with respect to their immune cell content and identified immunogenomic features associated with long-term survival. Our analysis demonstrates that tumors infiltrated by CD8+ T cells expressing higher levels of activation marker (PD1hi) along with TCR signaling genes and cytolytic T cell markers (IL2hi/TNF-αhi/IFN-γhi/GZMA-Bhi) extend survival, whereas survival benefit was absent for tumors infiltrated by anergic and hyperexhausted CD8hi T cells characterized by high expression of CTLA-4, TIM3, LAG3, and genes linked to PI3K signaling pathway. The computational approach of using robust and highly specific gene expression signatures to deconvolute the tumor microenvironment has important clinical applications, such as selecting patients who will benefit from checkpoint inhibitor treatment.
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