Using scRNAseq, Huang et al. found that TAMs and granulocytic MDSCs were increased in colorectal tumors and had high inhibitory signatures, including increased expression of SIRPA, which was associated with poor survival and tumor recurrence. In Sirpa-deficient mice, tumor growth was suppressed – an effect associated with increased antitumor Ccl8hi TAM and H2-Q10hi gMDSC subsets. Sirpa−/− macrophages showed increased phagocytic activity and antigen presentation, mediated enhanced T cell activation, and recruited T cells via Syk/Btk-dependent Ccl8 secretion. These TIME reprogramming effects were independent of interactions between Sirpα and CD47.
Contributed by Lauren Hitchings
ABSTRACT: Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa-/- mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8hi and gMDSC_H2-Q10hi subsets showing strong antitumor activity. Sirpa-/- macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa-/- macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer immunotherapy efficacy.