A Combination of Chemotherapy and Oncolytic Virotherapy Sensitizes Colorectal Adenocarcinoma to Immune Checkpoint Inhibitors in a cDC1-Dependent Manner |
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| Authors: | Nader El-Sayes Alyssa Vito Omar Salem Samuel Tekeste Workenhe Yonghong Wan Karen Mossman |
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| Affiliation: | 1.McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada; (N.E.-S.); (O.S.); (Y.W.);2.Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada;3.Department of Clinical Translation, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada;4.Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada; |
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| Abstract: | Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1. This combination induced the infiltration of CD8+ and CD4+ T cells into the tumor and the upregulation of gene signatures associated with the chemoattraction of myeloid cell subsets. When combined with immune checkpoint therapy, the combination promoted the infiltration of activated type 1 conventional dendritic cells (cDC1s) into the tumor. Furthermore, we found this combination strategy to be dependent on cDC1s, and its therapeutic efficacy to be abrogated in cDC1-deficient Batf3−/− mice. Thus, we demonstrated that the adjuvanticity of dMMR CRCs can be improved by combining low-dose chemotherapy and oncolytic HSV-1 in a cDC1-dependent manner. |
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| Keywords: | colorectal cancer immunotherapy immune checkpoint inhibitors oncolytic virus chemotherapy |
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