Project Summary/Abstract: Macrophages are one of the major cellular elements in the tumor
microenvironment (TME). Tumor associated macrophages (TAMs) markedly outnumber dendritic cells (DCs)
and represent a prominent population of antigen presenting cells (APCs) in the TME. Assessment of their
number and distribution in human solid tumors provides elusive and paradoxical information regarding their
roles in human tumor immunity. Based on studies in murine systems, macrophages are historically classified
into M1 and M2 subsets. However, the phenotype, characteristics, and functions of macrophages are
determined by the environmental milieu, in which macrophages reside. Like the PD-L1/PD-1 pathway, we aim
at identification of previously unknown immune resistance target(s), which may be potentially targetable with
specific monoclonal antibody (mAb). Hence, we have attempted to explore the relationship between
transmembrane proteins in APCs (and tumor cells as well) and ICB efficacy in patients with cancer and in
tumor bearing animal models. We discovered that (a) membrane-spanning 4-domains subfamily A member
7 (MS4A7) was predominantly expressed in TAMs; (b) MS4A7 contributed to poor anti-tumor immunity and
correlated with immune resistance to ICB in both in humans and mice; and (c) MS4A7 interacted with and
prevented TREM2 (Triggering receptor expressed on myeloid cells 2) cleavage, resulting in a reduced
expression of key functional genes (such as MHC and CD86) in macrophages, an impaired macrophage-
mediated phagocytosis, and a reduced T cell activation. Based on these surprising and novel findings, our
central hypothesis is that MS4A7 endows TAM phenotype and shapes ICB efficacy; and blocking MS4A7 and
its pathway could reprogram TAMs. Therefore, MS4A7 is a myeloid cell associated, previously unknown
immune resistance membrane protein, and a potential novel ICB target. In this application, we propose two
specific aims with 7 subaims to test this central hypothesis mechanistically, functionally, and translationally by
engaging bioinformatics, genomic, proteomic, immunological tools, and novel MS4A7-neutralizing antibodies.
Aim 1 is to test our hypothesis that MS4A7 contributes to TAM-mediated immune suppression.
Aim 2 is to test our hypothesis that the MS4A7-TREM2 axis controls TAMs and tumor immunity.
The proposal will define the role of MS4A7 in tumor immunity and the underlying molecular mechanisms in
both human and mouse cancers, set the stage to explore other likely cancer immune-relevant membrane-
spanning family members, and provide a proof of principle that targeting specific membrane-spanning protein
may augment tumor immunity and sensitize ICB efficacy.