Daytime SHP2 inhibitor dosing, when immune cell numbers are elevated, shrinks neurofibromas

Loss of NF1 in Schwann cells leads to activation of the RAS-MAPK pathway, followed by immune cell recruitment and development of benign nerve tumors (PNFs). MEK inhibitors, which shrink most PNFs, also reduce tumor-associated myeloid cells. We tested whether SHP2 inhibition, predicted to block RAS-MAPK signaling and exert immunomodulatory effects, alters tumor volume or the immune microenvironment in PNFs, using flow cytometry and single-cell RNA sequencing. We found that both cobimetinib and daytime RMC-4550 similarly reduced tumor volume. The abundance of CD163-negative PNF-associated macrophages, derived from circulating monocytes, correlated with tumor size. Combining SHP2 inhibition with anti-PD1 altered tumor monocyte phenotype and reversed SHP2-mediated tumor shrinkage. Diurnal patterns of monocyte trafficking were disrupted in tumor-bearing mice, and SHP2 inhibition reduced tumor volume only when administered during the day, when myeloid infiltration was low. These findings suggest that SHP2 inhibitor-driven tumor shrinkage requires targeting monocyte-derived macrophages and is influenced by the timing of drug administration.