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Cell and Gene Therapy 2018 & Clinical Microbiology Congress 2018
Biomedical Research
|
ISSN: 0976-1683
|
Volume 29
S e p t e m b e r 1 0 - 1 1 , 2 0 1 8 | D u b l i n , I r e l a n d
allied
academies
Joint Event on
CLINICAL AND MEDICAL MICROBIOLOGY
CELL AND GENE THERAPY
&
World Congress on
International Conference on
Biomed Res 2018, Volume 29 | DOI: 10.4066/biomedicalresearch-C3-008
TARGETING CD38 ON TUMOR CELLS TO REVERSE THE RESISTANCE TO
ANTI-PD-1/PD-L1 IMMUNOTHERAPY OF CANCER
Limo Chen, Lixia Diao, B Leticia Rodriguez, Ignacio I Wistuba, Jing Wang, John V Heymach, F Xiao-Feng Qin
and
Don L Gibbons
The University of Texas MD Anderson Cancer Center, USA
A
lthough strategies incorporating immune checkpoint inhibition are achieving unprecedented successes and rapidly being
incorporated into standard of care regimens for lung cancer patients, high rates of therapeutic resistance limit their potential
efficacy. Thus, successful immunotherapy of lung cancer requires a thorough understanding of the biological process of resistance.
In immunocompetent syngeneic and K-ras
LA1/+
p53
R172HΔg/+
spontaneous animal models of lung cancer, we have explored the
resistance mechanisms using pharmacological and genetic approaches (PD-1/PD-L1 monoclonal antibody treatment and CRISPR/
Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. More importantly, to
determine the applicability to patients, 793 lung cancer specimens were immunohistochemically stained for CD38, and multiple
large independent patient datasets (TCGA, PROSPECT, BATTLE-2) of non-small cell lung cancer (~1430 tumors) were analyzed by
using integrated bioinformatics. We identified the up-regulation of CD38 on tumor cells as the marker of resistance to anti-PD-1/
PD-L1 treatment. The same resistance mechanism caused by CD38 was also observed in PD-L1 KO mice bearing PD-L1 KO Lewis
lung tumors edited with the CRISPR/Cas9 system.
In vitro
and
in vivo
studies revealed that CD38 inhibited CD8 T cell function via
adenosine receptor signaling, and that CD38 blockade served as an effective strategy to overcome the treatment resistance to
PD-1/PD-L1 axis blockade. In lung cancer patients, 15-23% of cases exhibited positive staining for CD38 on tumor cells, showing a
great potential benefit for treatment. Multiple large datasets of lung cancer patients suggested a strong correlation between CD38
and an intratumoral immune signature.