Eosinophils inhibit response to chemotherapy: mechanisms, preclinical and clinical study in mesothelioma

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive cancer
affecting the pleura and is mainly caused by asbestos exposure. Prognosis for MPM
patients remains globally poor notably due to the advanced stage of the disease at
presentation and because of its resistance to available treatments. Therapeutic
approaches have been disappointing, and treatments used have not proven their ability
in significantly prolonging survival in comparison to supportive care. The possibility
of curative resection is extremely rare and the impact of chemotherapy on the outcome
of patients with MPM is still limited. The biological mechanisms that mediate this
partial or lack of response are unknown. However, emerging evidence indicates that
the tumor microenvironment (TME) is a key factor. Although only 0.5% to 1.7% of
patients with malignant tumors may present eosinophilia, MPM is one of the cancers
where excess of eosinophils in the peripheral blood has a strong association with
survival.
In the first part of my thesis, a retrospective study of MPM patients’ clinical data
was conducted. Results show that a cutoff of 220 eosinophils/μL of blood splits the
patients’ cohort into two groups with significantly different median overall survival
after chemotherapy. The corresponding two-year overall survival rates are also
significantly different. The response to standard chemotherapy is significantly
reduced in the AEC > 220/μL subset, based on progression-free survival and disease
control rate.
The second part of my work consisted in confirming the observed correlation in
patients, by using an in vitro model based on the EOL1 cell line and primary
eosinophils isolated from healthy donors’ blood. In vitro analyses in 2D and spheroids
models highlight that eosinophils’ supernatant inhibits MPM cells response to
chemotherapy. Transcriptomic data reveals that protein binding, response to stimulus
and intracellular vesicle are the most significantly enriched gene ontology terms.
Experimental evidence further demonstrates that recombinant galectin-10 to the
culture medium inhibits the proapoptotic effect of cisplatin and pemetrexed.
Conversely, depletion of CLC-P/Gal10 from the medium suppresses the inhibitory
effect of eosinophil supernatant. Finally, mice experiments highlight potential
management of patients presenting an excess of blood eosinophils prior to
chemotherapy administration.
This thesis reveals a potential novel prognosis marker for MPM patients with
experimental, preclinical and clinical evidence supporting the role of eosinophils in
the pathogenesis and therapy of MPM. This offers new prospect for an oriented and
personal care.