In a recent study published in Science, He et al. investigated the role of CD5 on
dendritic cells (DCs) in priming effector T cells.
1
By proving the importance of CD5 in engaging effective antitumor immune responses,
they highlighted the untapped potential of CD5 for targeted immunotherapy.
Checkpoint-inhibitor immunotherapy can safely be considered as a revolutionary development
in cancer treatment. However, serious side-effects are frequent, prediction of therapy
success is still challenging and nonresponding patients are omnipresent. Improved
understanding of the interaction of antigen-presenting with effector cells, especially
in the tumor microenvironment (TME), might lay the foundation for advanced therapeutic
approaches. DCs, the most important antigen-presenting cells, are further divided
in CD5+ and CD5- subsets with differential capacity for T cell activation. Thus, He
et al. scrutinized the functional role of CD5 in immunologic interactions and its
prognostic value for patient survival.
One major finding was the induction of T cell proliferation by CD1c+ CD5+ DCs isolated
from both skin and lymph nodes (see Fig. 1a). T cell proliferation was additionally
accompanied by increased production of the activation markers IFNγ and TNFα as well
as the effector molecules granzyme B and perforin. Moreover, T cell proliferation
could further be improved by increased expression levels of CD5 on DCs. Beside the
dependence of stimulating DC capacity on CD5, the authors also showed strengthened
immune response against classical viral recall antigens (influenza, Epstein Barr and
cytomegalovirus) when these were presented on CD5+ DCs. The stimulation of T cells
with antigen-loaded CD5- or CD14+ DCs was significantly less effective.
Fig. 1
The role of CD5 in tumor immunology and therapeutic chances. a CD5+ cDC2 play an important
role in tumor immunology. (upper left) Under influence of IL-6, hematopoietic progenitor
cells differentiate into CD5+ cDC2. (upper right) CD5+ cDC2 induce strong proliferation
of CD5high T cells, while proliferation induced by CD5- cDC2 is less effective and
limited to CD5low T cells. (lower left) Successful T-cell-induced tumor cell elimination
depends on CD5 expression on both cDC2 and T cells. Beside interaction of CD5+ cDC2
with CD5 on T cells, yet unidentified receptors might be involved, too. (lower right)
Anti-PD-1 therapy is most effective when CD5+ cDC2 are present in the TME and can
induce activation and proliferation of CD5+ T cells. b CD5’s role in tumor immunology
imply therapeutic chances. (upper left) The use of cross-linking antibodies could
enhance antitumor response. (upper right) CD5 could be used for the selection of DCs
instead of CD14 to improve T cell activating capacity. (lower left) Biopsy screening
for CD5+ cDC2 might guide therapeutic decisions for immunotherapy. (lower right) In
the autoimmune disease situation, blocking CD5 could regulate immune activity. cDC2
conventional dendritic cells 2, IL-6 interleukin 6, MHC major histocompatibility complex,
PD-1 programmed cell death protein 1, TCR T cell receptor. Created with BioRender.com
Further, in vivo experiments showed the functional dependence on CD5+ DCs for strong
antitumor responses. When CD5+ DC were depleted, a majority of mice was unable to
initiate a forceful immune reaction involving CD4+ and CD8+ effector T cells, while
mice with unaltered DCs could and did successfully reject their tumors.
Aside from CD5’s role on DCs, the authors also elucidated CD5 expression on T cells
and showed that it very closely mirrored the CD5 expression of DCs. It had been clear,
that the antiquated T cell marker CD5 is important for T cell receptor signaling fine
tuning and for protection from activation-induced cell death.
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Historically, CD5 has been considered as a purely negative regulator but more recent
data imply, that via signaling through NF-κB, it helps maintaining higher levels of
intracellular IκBα, which enables CD5+ T cells to better persist as effector/memory
cells.
3
Together with the data of the Klechevsky laboratory on CD5-mediated inhibition of
apoptosis in DCs, this hints towards a general and assumedly context-dependent mechanism.
Remarkable differences regarding CD5-proficient and CD5-deficient immune cells were
observed in experimental immunotherapy. The authors validated the necessity of CD5
on both DCs and T cells for noteworthy tumor regression induced by immune checkpoint
inhibitor treatment (anti-PD-1 or anti-CTLA-4).
Further, He et al. validated older observations of reduced CD5 expression in the TME
compared to healthy tissue, hinting at a tumor-induced downregulation.
4
The parallel to specific modulation of known immune checkpoint molecules like PD-1
in the TME is striking. While immune checkpoints like PD-1 are expressed on T cells,
they can also be found on CD5+ DCs. Taking the demonstrated utmost importance of CD5
into account, its induction by immune checkpoint inhibitors could restore tumor-suppressed
DC activity via inducing CD5 expression and the proliferation of CD5+ DCs. The subsequent
activation of tumor-reactive T cells could tip the scale back in the direction of
equilibrium or even tumor elimination. This hypothesis is further strengthened by
the increase of IL-6 in the TME of anti-PD1-treated mice and the observation of IL-6-dependent
progenitor cell differentiation into CD5+ DCs.
The study of He and coworkers adds further important pieces to the puzzle of tumor-immune
cell interaction in the TME of affected patients. Moreover, it raises a number of
important questions like the role of CD5 on further immune cell types like B or NK
cells and their subsets as well as their potential involvement in the CD5-dependent
immune regulation. B cells with their strong antigen-presenting capacity are regularly
present in the TME, but contrary to DCs and T cells, CD5+ B cells seem to be suppressive,
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thereby highlighting the duality in function of CD5, which must be clarified.
However, CD5+ DCs seem to be pivotal for immunotherapy success. Retrospective analyses
of tumor patient cohorts treated with checkpoint inhibitors should be performed to
clarify CD5’s therapeutic impact. If significantly correlating with response, CD5
could indeed be the desired biomarker to amend or even overcome the insufficient predictive
significance of immune infiltration, PD-L1 expression or tumor mutational burden (see
Fig. 1b).
For cellular therapy approaches, the results of He and coworkers have even stronger
implications. Currently, DCs are mainly selected based on CD14 expression. If CD5
expression is better suited than CD14 to define T cell-activating DCs, CD5 determination
or even selection should be taken into consideration for future DC vaccine preparation.
As the authors also showed the positive effects of crosslinking and agonistic CD5
antibodies for boosting T cell responses, further research should focus on that, too.
However, since CD5 might be a crucial factor for initiating strong immune reactions,
this opens up the possibility of targeting this protein in overreacting immune cells
present in autoimmunity (see Fig. 1b). Thus, CD5-targeted therapy approaches must
be developed in a cell-specific and context-dependent manner to avoid undesirable
interferences in the CD5+ cells’ multifunctional network.
With a positive prognostic value of the CD5+ DC signature observed for melanoma, lung
squamous cell carcinoma, sarcoma, breast cancer, cervical squamous cell carcinoma
and endocervical adenocarcinoma patient cohorts, CD5 could be of ubiquitous importance
in a broad spectrum of tumors. But these data from The Cancer Genome Atlas (TCGA)
need to be validated in independent clinical sample collections to round out this
promising picture. It seems reasonable to assume that there will, for example, be
clear differences between hypermutated and non-hypermutated subgroups of a given cancer
type.
Ultimately, unraveling the presumable even more complex function of CD5 in cell fate
decisions under pathological conditions, will clarify its duality in function and
trigger therapeutic developments. Considering all aspects of CD5’s involvement in
antitumoral immune response, the study of He and colleagues might well mark the emergence
of a new phase particularly in immunotherapy.