LBA10 - Critical role of eosinophils during response to immune checkpoint blockade in breast cancer and other cancer types

Background

While the function of myeloid cells in cancer progression is widely studied, clinical data on their role during immune checkpoint blockade (ICB) response are limited. Better understanding of mechanisms contributing to response to ICB will provide a rationale for future combination treatments. By combining unbiased profiling of circulating immune cells in patients treated with ICB with mechanistic studies in mouse models, we aimed to study the role of myeloid cells in ICB response.

Methods

Multiparameter flow cytometry was performed on fresh blood from metastatic triple-negative breast cancer (TNBC) patients in the phase 2 TONIC trial (n=111) before start and after 3 cycles of anti-PD1. In addition, we used genetically engineered mouse models of primary and metastatic breast cancer for mechanistic studies. Finally, we validated our findings in 5 cancer types: metastatic non-small cell lung cancer (NSCLC; n=55), metastatic bladder cancer (n=34), metastatic mismatch repair deficient (dMMR) cancer (n=11) and early-stage dMMR (n=21) or MMR-proficient (pMMR) colon cancer (CC; n=17). RNA-sequencing was available for the TNBC and CC trials.

Results

A significant increase in circulating eosinophils during ICB was observed in patients with TNBC responding to ICB (p=0.002), but not in non-responders. In breast cancer mouse models that respond to dual ICB and cisplatin, we found that ICB response was lost upon depletion of eosinophils. Importantly, we found that an increase in eosinophils was also associated with response in NSCLC (p=0.03), early-stage pMMR CC (p=0.04) and in bladder cancer (p=0.05), but not in early-stage or metastatic dMMR tumors. Furthermore, we observed increased expression of eosinophil-related genes upon ICB in tumors of responders with metastatic TNBC and early-stage CC.

Conclusions

An increase in eosinophils is associated with ICB response in multiple tumor types and studies in mouse models uncovered a functional role for eosinophils during ICB response. These data indicate that eosinophils are mechanistically involved in response to ICB. Future combination strategies should consider engaging eosinophils to increase ICB efficacy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Dutch Cancer Society.

Disclosure

M. Chalabi: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squib; Research grant/Funding (institution): Roche/Genentech. M.S. van der Heijden: Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squib. W.S.M.E. Theelen: Research grant/Funding (institution): MSD; Research grant/Funding (institution): AstraZeneca. E.E. Voest: Research grant/Funding (institution): Bristol-Myers-Squib. K.E. de Visser: Research grant/Funding (institution): Roche; Advisory/Consultancy: Third Rock Ventures. M. Kok: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers-Squib; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Daiichi Sankyo. All other authors have declared no conflicts of interest.