CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

Biasci, D., Smoragiewicz, M., Connell, C. M., Wang, Z., Gao, Y., Thaventhiran, J. E., Basu, B., Magiera, L., Johnson, I. T., Bax, L., Gopinathan, A., Isherwood, C., Gallagher, F., Pawula, M., Hudecova, I., Gale, D., Rosenfeld, N., Barmpounakis, P., Popa, E. C., Brais, R., Godfrey, E., Mir, F., Richards, F., Fearon, D. T., Janowitz, T., Jodrell, D. (July 2020) CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. medRxiv. (Unpublished)

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Abstract

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anti-cancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition effects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all the immune cell types that participate in an integrated immune responses. Inhibiting CXCR4 in an experimental cancer medicine study by one-week continuous infusion of the small molecule inhibitor, AMD3100 (plerixafor), induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to non-infected tissues: rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human PDA and CRC by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > cancer types > colon cancer diseases & disorders > cancer > cancer types > colon cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:	Wang, Zhikai Gao, Ya Fearon, Douglas Janowitz, Tobias
Communities:	CSHL labs > Fearon lab CSHL labs > Janowitz lab
Depositing User:	Sasha Luks-Morgan
Date:	10 July 2020
Date Deposited:	08 Jun 2021 14:17
Last Modified:	29 Apr 2024 15:36
URI:	https://repository.cshl.edu/id/eprint/40201

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