TY - JOUR
T1 - cDC1 Vaccines Drive Tumor Rejection by Direct Presentation Independently of Host cDC1
AU - Ferris, Stephen T.
AU - Ohara, Ray A.
AU - Ou, Feiya
AU - Wu, Renee
AU - Huang, Xiao
AU - Kim, Sunkyung
AU - Chen, Jing
AU - Liu, Tian Tian
AU - Schreiber, Robert D.
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
N1 - Funding Information:
This work was supported by the NIH (R01AI150297, R01CA248919, and R21AI164142 to K.M. Murphy, R01CA240983 TO R.D. Schreiber,
Funding Information:
S.T. Ferris reports grants from Cancer Research Institute during the conduct of the study. R.D. Schreiber reports grants from NIH (NCI), Parker Institute for Cancer Immunotherapy, SU2C, Asher Biotherapeutics, Jounce Therapeutics, NGM Biotherapeutics; and grants from Sensei Biotherapeutics during the conduct of the study; personal fees from A2 Biotherapeutics, Arch Oncology, Asher Biotherapeutics, Codiak Biosciences, Jounce Therapeutics, NGM Biopharmaceu-ticals, Sensei Biotherapeutics; and other support from Cancer Immunology Research outside the submitted work. K.M. Murphy reports grants from NIH; and grants from NIH during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
This work was supported by The NIH (R01AI150297, R01CA248919, and R21AI164142 to K.M. Murphy, R01CA240983 TO R.D. Schreiber, and F30CA247262 to R.W.) S.T. Ferris and X. Huang are Cancer Research Institute Irvington Fellows supported by The Cancer Research Institute.
Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2022/8
Y1 - 2022/8
N2 - As a cell-based cancer vaccine, dendritic cells (DC), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDC), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor-specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared antitumor responses induced by GMDCs and cDC1 in Irf8 þ32–/– mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8þ T cells in vitro. However, injection of GMDCs into tumors in Irf8 þ32–/– mice did not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 þ32–/– mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8þ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce antitumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for antitumor therapy.
AB - As a cell-based cancer vaccine, dendritic cells (DC), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDC), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor-specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared antitumor responses induced by GMDCs and cDC1 in Irf8 þ32–/– mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8þ T cells in vitro. However, injection of GMDCs into tumors in Irf8 þ32–/– mice did not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 þ32–/– mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8þ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce antitumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for antitumor therapy.
UR - http://www.scopus.com/inward/record.url?scp=85135597753&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-21-0865
DO - 10.1158/2326-6066.CIR-21-0865
M3 - Article
C2 - 35648641
AN - SCOPUS:85135597753
SN - 2326-6066
VL - 10
SP - 920
EP - 931
JO - Cancer immunology research
JF - Cancer immunology research
IS - 8
ER -