In this issue of Cancer Immunology Research, Ferris and colleagues demonstrate that type 1 conventional DC (cDC1) vaccines drive tumor rejection through direct antigen presentation, without the need of endogenous cDC1. This suggests that cDC1-based vaccines could represent an optimal strategy to induce antitumor immunity in patients.

See related article by Ferris et al., p. 920 (7).

Dendritic cells (DC) are professional antigen-presenting cells specialized in the uptake, processing, and presentation of antigen to naïve T cells to elicit primary immune responses. DCs are classified as conventional (c)DCs (consisting of two subsets, cDC1 and cDC2) and plasmacytoid DCs, and can be further divided into migratory DCs (mDC) or lymphoid-resident DCs (rDC). mDCs are located in peripheral tissues and comprise cDC1 and cDC2 subsets. They migrate to draining lymph nodes in a CCR7-dependent manner after antigen encounter to induce tolerance in the steady state or immunity toward pathogens or tumor cells. Previous studies suggest cDC1s dominantly prime CD8+ T cells through antigen cross-presentation, whereas cDC2s mainly prime CD4+ T cells. It has also been proposed that mDCs gather local antigen, whereas rDCs acquire antigen from lymphatic drains carrying apoptotic bodies and peptides, as well as cellular sources such as DC vaccines (1). The development of DC subsets depends on FLT3L, and their differentiation states are regulated by multiple factors, including the growth factor GMCSF.

DC vaccines for cancer therapy have been developed using cells generated from culturing peripheral blood monocytes or bone marrow cells with GMCSF (+/− IL4), referred to GMDCs. Multiple clinical studies using GMDC vaccines report modest antitumor immune responses and clinical benefits (2). One limitation of GMDC vaccines is the dependence on host DCs for T-cell activation. Initially, GMDCs were thought to directly stimulate host T cells through in vivo presentation of tumor antigen. However, CD4+ T-cell activation by GMDC vaccination requires MHC-II expression by host cDCs (3), and CD4+ or CD8+ antigen-specific T-cell responses induced by GMDCs can be restored by selective MHC reexpression on DCs in the context of MHC deficiency (1). Antigen-specific CD8+ T-cell activation is not observed in mice that lack cDC development (4). These results indicate that GMDCs do not present antigens directly to host T cells, but act as a source of antigen that is transferred and processed by host cDCs (5). In addition, tumor rejection requires MHC-I/-II expression by cDC1 for both direct CD8+ and CD4+ T-cell priming against tumor-derived antigens and for orchestration of their cross-talk for optimal antitumor immunity (5).

Because cDC1 can directly prime both CD4+ and CD8+ T cells, Ferris and colleagues investigated whether cDC1 vaccines, unlike GMDC vaccines, could induce direct tumor antigen presentation to host T cells, independently of host DCs (6). To address this, they develop a new mouse model that lacks endogenous cDC1 and cannot reject immunogenic fibrosarcomas. They compare antitumor responses induced by intratumoral injection of GMDCs and cDC1. Interestingly, they observe that although GMDCs and cDC1 can cross-present cell-associated antigens to CD8+ T cells in vitro, injection of GMDCs into tumors does not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1 into tumors results in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8+ T cells, and tumor rejection, which did not require in vitro loading of cDC1 with antigen, indicating that antigen uptake in vivo is sufficient to induce antitumor responses. Finally, cDC1 vaccination shows abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results demonstrate for the first time that cDC1 vaccines drive tumor rejection through direct antigen presentation, without the need of endogenous cDC1. cDC1-based vaccination could represent a promising strategy to induce antitumor immunity in patients and argues for the development of an optimized in vitro protocol for cDC1 generation in humans.

No disclosures were reported.

1.
Yewdall
AW
,
Drutman
SB
,
Jinwala
F
,
Bahjat
KS
,
Bhardwaj
N
.
CD8+ T cell priming by dendritic cell vaccines requires antigen transfer to endogenous antigen presenting cells
.
PLoS One
2010
;
5
:
e11144
.
2.
Saxena
M
,
Bhardwaj
N
.
Re-emergence of dendritic cell vaccines for cancer treatment
.
Trends Cancer
2018
;
4
:
119
37
.
3.
Abakushina
EV
,
Popova
LI
,
Zamyatnin
AA
Jr
,
Werner
J
,
Mikhailovsky
NV
,
Bazhin
AV
.
The advantages and challenges of anticancer dendritic cell vaccines and NK cells in adoptive cell immunotherapy. Vaccines. 2021;9:1363
.
4.
Kleindienst
P
,
Brocker
T
.
Endogenous dendritic cells are required for amplification of T cell responses induced by dendritic cell vaccines in vivo
.
J Immunol
2003
;
170
:
2817
23
.
5.
Ferris
ST
,
Durai
V
,
Wu
R
,
Theisen
DJ
,
Ward
JP
,
Bern
MD
et al
.
cDC1 prime and are licensed by CD4(+) T cells to induce anti-tumour immunity
.
Nature
2020
;
584
:
624
9
.
6.
Ruhland
MK
,
Roberts
EW
,
Cai
E
,
Mujal
AM
,
Marchuk
K
,
Beppler
C
et al
.
Visualizing synaptic transfer of tumor antigens among dendritic cells
.
Cancer Cell
2020
;
37
:
786
99
.
7.
Ferris
ST
,
Ohara
RA
,
Ou
F
,
Wu
R
,
Huang
X
,
Kim
S
, et al
.
cDC1 vaccines drive tumor rejection by direct presentation independently of host cDC1
.
Cancer Immunol Res
2022
;
10
:
920
31
.