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2017 ; 6
(10
): e1353857
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PD-1 blockade at the time of tumor escape potentiates the immune-mediated
antitumor effects of a melanoma-targeting monoclonal antibody
#MMPMID29123966
They L
; Michaud HA
; Becquart O
; Lafont V
; Guillot B
; Boissière-Michot F
; Jarlier M
; Mollevi C
; Eliaou JF
; Bonnefoy N
; Gros L
Oncoimmunology
2017[]; 6
(10
): e1353857
PMID29123966
show ga
Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as
therapeutics in many malignancies and their capacity to mobilize the host
immunity puts them at the forefront of anti-cancer immunotherapies. Both innate
and adaptive immune cells have been associated with the therapeutic activity of
such antibodies, but tumor escape from mAb-induced tumor immune surveillance
remains one of the main clinical issues. In this preclinical study, we grafted
immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell
line and treated them with the TA99 TA-targeting mAb to analyze the immune
mechanisms associated with the tumor response and resistance to TA99 monotherapy.
In immunocompetent mice TA99 treatment strongly increased the fraction of CD8 and
CD4 effector T cells in the tumor compared with isotype control, highlighting the
specific immune modulation of the tumor microenvironment by TA99. However, in
most mice, TA99 immunotherapy could not prevent immune effector exhaustion and
the recruitment of regulatory CD4 T cells and consequently tumor escape from
immune surveillance. Remarkably, anti-PD-1 treatment at the time of tumor
emergence restored the Th1 effector functions of CD4 and CD8 T cells as well as
of natural killer and ??T cells, which translated into a significant slow-down of
tumor progression and extended survival. Our findings provide the first evidence
that PD-1 blockade at the time of tumor emergence can efficiently boost the host
anti-tumor immune response initiated several weeks before by the TA-targeting
mAb. These results are promising for the design of combined therapies to
sensitize non-responder or resistant patients.
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